static-content.springer.com10.1038/s41557-020-0475-7... · ArtiCLeS Cobalt-catalysed C–H methylation for late-stage drug diversification Stig D. Friis1, Magnus J. Johansson 1 and

Articleshttps://doi.org/10.1038/s41557-020-0475-7

Cobalt-catalysed C–H methylation for late-stage drug diversificationStig D. Friis1, Magnus J. Johansson 1 ✉ and Lutz Ackermann 2 ✉

1Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 2Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Göttingen, Germany. ✉e-mail: [email protected]; [email protected]

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1

Supplementary Information

Cobalt-catalysed C−H methylation for late stage drug

diversification

Stig. D. Friis, Magnus J. Johansson and Lutz Ackermann

2

Content

I. General information 3

II. Catalyst preparation 4

III. General experimental procedures 5

IV. Literature survey (Main Text Fig. 1b) 6

V. Reaction optimization (Main Text Fig. 1d) 8

VI. Competition experiment (Main Text Fig. 2) 13

VII. Compatibility screening (Main Text Fig. 3) 15

VIII. Proposed de novo syntheses (Main Text Table 2 and Fig. 4) 19

IX. PhysChem-, DMPK- and primary activity data (Main Text Fig. 5) 24

X. Experimental and analytical data for products 31

XI. NMR spectra 43

XII. References 119

3

I. General information

General reagent and purification information. Anhydrous solvents were purchased from Sigma Aldrich, sparging with

N2 prior to use. Unless otherwise noted, all reagents were used as received. Co2(CO)8 was purchased from Strem Chemicals

Inc. Trimethylboroxine, Ag2CO3, K2CO3, and 1,2,3,4,5-pentamethylcyclopentadiene was purchased from Sigma Aldrich.

Solids were either weighed by hand or using a Mettler Toledo Quantos system for automated solid dispensing. Flash column

chromatography was performed using 60 Å, mesh 230-400 particle size silica gel from Sigma Aldrich or with prepacked

SNAP silica gel columns on a Biotage Isolera system. Purification by preparative reverse phase HPLC was performed on

a Kromasil C8 column (10 μm, 250x50 ID mm) with a flow rate of 100 mL/min over 25 minutes, using AcOH acidic

mobile phase (A: H2O/MeCN/AcOH 95/5/0.2, B: MeCN) or TFA acidic mobile phase (A: H2O/MeCN/TFA 95/5/0.2, B:

MeCN). Alternatively, preparative reverse phase HPLC was performed on a XBridge C18 column (10 μm 250x50 ID mm)

with a flow rate of 100 mL/min over 25 minutes, using basic mobile phase (A: H2O/MeCN/NH3 95/5/0.2, B: MeCN).

General analytical information. All new compounds were characterized by NMR spectroscopy and high-resolution mass

spectrometry (HRMS). NMR spectra were recorded on a Bruker Ultrashield 500 MHz spectrometer with a Bruker Cryo

Platform. NMR data are reported as follows: chemical shift in reference to the residual solvent peak (δ ppm), multiplicity

(s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, m =

multiplet), coupling constant (Hz), and integration. 1H NMR residual solvent peaks in respective deuterated solvents for

CHCl3 at 7.26 ppm, DMSO at 2.50 ppm, CH3OH at 3.31 ppm, CH3CN at 1.94 ppm, and CH3NO2 at 4.33 ppm. 13C NMR

residual solvent peaks in respective deuterated solvents for CHCl3 at 77.16 ppm, DMSO at 39.52 ppm, CH3OH at 49.00

ppm, CH3CN at 1.32 ppm, and CH3NO2 at 62.8 ppm. HPLC-MS analysis was performed on a Waters Acquity UPLC

system using an acidic mobile phase with a HSS C18 column (1.8 μm, 50 × 2.1 mm) or using a basic mobile phase with a

BEH C18 column (1.7 μm, 50 × 2.1 mm).

General safety information. Gaseous side-products (methane and ethane) are formed under the described reaction

conditions, causing a build-up of pressure in the reaction vials. Appropriate safety measure should be taken to mitigate

this risk. Keeping a 1:3 reaction volume to headspace ratio and performing high temperature (100 °C) reactions in crimp-

cap microwave vials behind a blast-shield are advised.

4

II. Catalyst preparation

Cp*Co(CO)I2 was prepared via a modified literature procedure1, by charging a dry 500 mL 2-necked flask, which was

fitted with a reflux condenser and a septum, with Co2(CO)8 (10.0 g, 29.2 mmol). The flask was then flushed with N2 for

10 min. Dry degassed dichloromethane (200 mL) was added, followed by 1,2,3,4,5-pentamethylcyclopentadiene (11.0

mL, 67.8 mmol), and the mixture was heated to gentle reflux. After 20 h, the volatiles were removed under vacuum,

avoiding exposure to air. Keeping the flask under a gentle flow of N2, dry degassed Et2O (100 mL) was added to the

resulting brown solid followed by careful addition of I2 (18.0 g, 70.9 mmol) in dry degassed Et2O (100 mL) [CAUTION:

Exothermic and CO-evolution]. After addition of half of the iodine solution the reaction mixture became difficult to stir;

continued addition of the iodine solution gradually made the solution easier to stir. After complete addition, the reaction

mixture was stirred at room temperature for 2 hours 30 min and then concentrated onto silica (150 mL). The resulting

semi-dry solid was loaded onto a short column of silica (D: 9 cm, L: 15 cm). Eluting first with 0-60% CH2Cl2 in heptane

(2.5 L) these initial fractions were discarded. Then eluting with 80% CH2Cl2in heptane (4.5 L), collecting the dark purple

eluate from the column. The volatiles were removed in vacuo and the resulting solid was dried under vacuum to afford

Cp*Co(CO)I2 (24.3 g, 87 %) as a black crystalline solid. 1H NMR (500 MHz, CDCl3) δ (ppm) 2.23 (s, 15H). 13C NMR (126 MHz, CDCl3) δ (ppm) 101.1 (5C), 11.6 (5C).

Cp*Co(PhH)(PF6)2 (4a) was prepared via a modified literature procedure2, by charging a dry 250 mL flask with

Cp*Co(CO)I2 (10.0 g, 21.0 mmol) and AlCl3 (14.5 g, 109 mmol), before evacuating and backfilling with N2 three times.

Dry degassed benzene (140 mL) was added and the reaction mixture was heated to 60 °C. After 18 h, the reaction

mixture was cooled to room temperature and carefully poured into an ice/water mixture (500 mL). The resulting mixture

was stirred for 15 min and then filtered through a pad of celite, washing with water. The liquid was transferred to a

separatory funnel and the organic layer was removed. A solution of NH4PF6 (7.25 g, 44.5 mmol) in water (20 mL) was

added to the stirring aqueous phase (1.5 L total volume) causing the precipitation of a brown solid. After stirring for 15

min, the solid was collected by gravitational filtration and washed with water (2*10 mL) and Et2O (2*50 mL). The brown

solid, still wet, was dissolved in refluxing acetone (3.5 L) and filtered warm, before Et2O (3.5 L) was added causing the

precipitation of a light brown solid. After cooling to room temperature, the solid was collected by filtration and dried

under vacuum. Repeating this recrystallization process resulted in the formation of a yellow solid which was collected by

filtration and dried under vacuum to afford Cp*Co(PhH)(PF6)2 (6.41 g, 54 %). 1H NMR (500 MHz, CD3NO2) δ (ppm) 7.37 (s, 6H), 2.22 (s, 15 H). 13C NMR (126 MHz, CD3NO2) δ (ppm) 112.7 (5C),

106.9 (6C), 11.7 (5C). 19F NMR (471 MHz, CD3NO2) δ (ppm) -75.8 (d, JF-P = 707 Hz). 31P NMR (202 MHz, CD3NO2) δ

(ppm) -147.1 (septet, JP-F = 707 Hz).

5

III. General experimental procedures

General Procedure A (Main Text Figure 2)

On the benchtop, a 20 mL vial was charged with Cp*Co(PhH)(PF6)2 (28.1 mg, 0.05 mmol), Ag2CO3 (276 mg, 1.00

mmol), K2CO3 (138 mg, 1.00 mmol) and substrate (0.50 mmol). The vial was moved into a glovebox under N2, where 2-

methyltetrahydrofuran (5.0 mL) and trimethylboroxine (212 µL, 1.50 mmol) were added. The vial was closed, taken out

of the glovebox and heated to 60 °C. After 16 hours, the reaction mixture was cooled to room temperature analysed by

HPLC-MS. The volatiles were removed in vacuo before the residue was purified by automated flash column

chromatography. The relevant fractions were collected, combined, and concentrated to give the desired product(s).

In cases where a mixture of products and/or starting material was obtained, their ratios were determined by 1H NMR and

yields calculated based on this analysis. The individual compounds were subsequently separated by preparative reverse

phase HPLC to confirm their identity.

General Procedure B (Standard Conditions, Main Text Figure 4)

On the benchtop, a 20 mL vial was charged with Cp*Co(PhH)(PF6)2 (56.2 mg, 0.10 mmol), Ag2CO3 (276 mg, 1.00

mmol), K2CO3 (138 mg, 1.00 mmol), and substrate (0.50 mmol). The vial was moved into the glovebox, where 2-

methyltetrahydrofuran (5.0 mL) and trimethylboroxine (212 µL, 1.50 mmol) was added. The vial was closed, taken out

of the glovebox and heated to 60 °C. After 16 h, the reaction mixture was cooled to room temperature and analysed by

HPLC-MS. The solid material was removed by filtration though a plug of celite, washing with EtOAc or EtOAc and

MeOH. After removal of the volatiles in vacuo, the crude material was dissolved in DMSO (5 mL) and purified by

preparative reverse phase HPLC. The relevant fractions were collected, combined, and lyophilized to afford the desired

product.

General Procedure C (LSF Conditions, Main Text Figure 4)

[CAUTION: The reactions are heated above the boiling point of some reagents and gaseous side-products are formed

during the reaction. Keep a 1:3 reaction volume to headspace ratio and perform reactions in crimp-cap microwave

vials.]

On the benchtop, a 10 mL crimp-cap vial was charged with Cp*Co(PhH)(PF6)2 (141 mg, 0.25 mmol), Ag2CO3 (207 mg,

0.75 mmol), K2CO3 (104 mg, 0.75 mmol), and substrate (0.25 mmol). The vial was moved into a glovebox under N2,

where 2-methyltetrahydrofuran (2.5 mL) and trimethylboroxine (212 µL, 1.50 mmol) were added. The vial was closed,

taken out of the glovebox, and heated to 100 °C. After 16 h, the reaction mixture was cooled to room temperature and

analysed by HPLC-MS. The solid material was removed by filtration though a plug of celite, washing with EtOAc or

EtOAc and MeOH. After removal of the volatiles in vacuo, the crude material was dissolved in DMSO (5 mL) and

purified by preparative reverse phase HPLC. The relevant fractions were collected, combined, and lyophilized to afford

the desired product.

6

IV. Literature survey (Main Text Figure 1b)

References to a representative selection of transition metal-catalysed C–H activation-alkylation protocols, as presented in

Main Text Figure 1b in the main text, are given below (Supplementary Figure 1). As highlighted, the majority of work

resides in the lower left quadrant of the figure, and protocols, which can take advantage of the more appealing boron-

based alkyl sources exclusively require a precious transition metal catalyst. Notably, no protocol which can take

advantage of a broad scope of directing groups are known. For a comprehensive review of the C-H activation-alkylation

literature, the reader is referred to the excellent reviews by Zhang, Evano and Ackermann3-5.

We have not included hydroarylation-type chemistry, since this does not enable C–H methylation.

Chemistries that require a Grignard reagent as a stoichiometric reagent is classified accordingly even if this is not the

source of the installed alkyl group.

R-BF3K or

R-B(OR’)2

Pd: Yu et al.6 Pd: Yu et al. 7

Pd: Gevorgyan et al. 8 Ru: Ackermann et al. 9

*Ir: Sorensen et al. 10 *Pd: Yu et al. 11 *Pd: Yu et al. 12

*Pd: Yu et al. 13 *Rh: Li et al. 14

*Pd: Sanford et al.15

This work

Co: Ackermann et al.

R-ZnX or

R4Sn or

(RO)2

Pd: Yu et al. 16 Fe: Nakamura et al. 17

Mn: Ackermann et al. 18 Pd: Yu et al. 19 Co: Cai et al.20

R-X or

R3Al

Pd: Daugulis et al. 21 Ni: Ackermann et al. 22

Co: Xu et al. 23 Ru: Ackermann et al. 24

Ru: Ackermann et al. 25 Pd: Novák et al. 26

Ru: Yi et al. 27 Fe: Nakamura et al. 28

R-MgX Fe: Cook et al. 29

Fe: Ackermann et al. 30 Co: Yoshikai et al. 31

Co: Yoshikai et al.32 Co: Nakamura et al. 33 Co: Ackermann et al. 34

Mn: Nakamura et al. 35

Specialized

DG 1-2 different

DG 3-5 different

DG

>10 different DG

Figure 1. References for the literature survey of transition metal catalysed C–H activation-alkylation (Main Text Figure 1b). References are categorized

according to number of applicable directing groups (DG) (x-axis) and the nature of the required alkyl source (y-axis). *See benchmarking analysis

below.

7

Benchmarking analysis

Sorensen et al.10

Applicable directing groups: N-Aryl imine (generated in situ)

Comment: Ir-catalysis, C(sp2)−H activation, one methylation example (18% yield). No LSF

of drugs or advanced intermediates thereof.

Representative examples

Yu et al.11

Applicable directing groups: Pyridine

Comment: Pd-catalysis, C(sp2)−H and C(sp3)−H activation, enantioselective, no methylation

example. No LSF of drugs or advanced intermediates thereof.


Yu et al.12

Applicable directing groups: Carboxylic acid (benzoic acids and phenylacetic acids)

Comment: Pd-catalysis, C(sp2)−H activation, two methylation examples of which one

produces a MedChem relevant molecule (not LSF).


Yu et al.13

Applicable directing groups: Pyridine and pyrazole

Comment: Pd-catalysis, C(sp2)−H and C(sp3)−H activation, methylation focused. No LSF of

drugs or advanced intermediates thereof.


Li et al.14

Applicable directing groups: Pyridine (incl pyrimidine), oxime and amide (+ specialized DG)

Comment: Rh-catalysis, C(sp2)−H activation, methylation focused, one amide example (43%

yield). No LSF of drugs or advanced intermediates thereof.


Sanford et al.15

Applicable directing groups: Pyridine, primary anilide, secondary cyclic anilide

Comment: Pd-catalysis, C(sp2)−H activation, methylation focused. No LSF of drugs or

advanced intermediates thereof.


8

V. Reaction optimization

Data obtained from a selection of the reactions that were performed to optimize the reaction conditions for this cobalt-

catalyzed C–H methylation reaction is shown below. The data shown was obtained by LCMS and is based on the relative

intensities of the product peak(s) vs. substrate peak in the UV chromatogram i.e. conversion to product.

General procedure for reaction optimization

The reactions were setup using 96-well Para-dox plates with 1 mL glass vials using 0.02-0.05 mmol substrate.

On the benchtop or in a glovebox under nitrogen, the vials were charged with all solids. The plate was move into a

glovebox under nitrogen, where solvent was added followed by addition of liquid reagents. The plate was closed, taken

out of the glovebox and heated under stirring (500-700 rpm). After 15 – 18 hours the reactions mixtures were allowed to

cool to room temperature, before they were diluted with MeCN and analyzed by LCMS.

See Supplementary Figure 2-9 for reaction details and results. Not all optimization data is shown.

Base, oxidant, alkyl source, and solvent

Alkyl source Oxidant Solvent Base

A-D Me3B3O3 A, E AgOAc 1-6 1,2-Dichloroethane 1, 7 K2CO3 E-H Me-Bpin B, F Ag2CO3 7-12 Dioxane 2, 8 Cs2CO3 C, G MnF3 3, 9 K3PO4 D, H Cu(OAc)2 4, 10 KF 5, 11 TMSONa 6, 12 tBuONa

Results

Figure 2. Evaluation of base, oxidant, alkyl source, and solvent.

9

Oxidant

Plate Layout

Amount Oxidant (equiv) Oxidant

A 0.25 1 AgOAc B 0.50 2 Ag2CO3 C 0.75 3 MnF3 D 1.00 4 Cu(OAc) 2 E 1.25 5 NaOCl3 F 1.50 6 K2S2O8 G 2.00 7 Oxone H 3.00 8 CAN 9 DDQ 10 PhI(OAc)2 11 SelectFluor 12 Na2O2

Results

Figure 3. Evaluation of oxidants and the amount required.

10

Solvent

Plate Layout

Additive solvent (10%) Main solvent (90%)

A “Main solvent” 1 1,2-Dichloroethane B 3,3,3-Trifluoroethanol 2 Dioxane C 1,1,1,3,3,3-Hexafluoro-2-propanol 3 3,3,3-Trifluoroethanol D MeCN 4 1,1,1,3,3,3-Hexafluoro-2-propanol E AcOH 5 PhCF3 F 1,8-Diazabicyclo[5.4.0]undec-7-ene 6 Cyclohexane G DMSO 7 DMSO H N-Methyl-2-pyrrolidone 8 2-Methyltetrahydrofurane 9 MeCN 10 PhMe 11 Cyclopentylmethylether 12 tBuOH

Results

Figure 4. Evaluation of solvent and potential solvent additives.

Stoichiometry

Plate Layout

Concentration Amount Me3B3O3 Amount K2CO3 Amount Ag2CO3 Amount Catalyst

A, E 0.50 M A-D 2.0 equiv 1-6 2.0 equiv 1-3, 7-9 1.0 equiv 1, 4, 7, 10 5 mol% B, F 0.25 M E-H 4.0 equiv 7-12 4.0 equiv 4-6, 10-12 2.0 equiv 2, 5, 8, 11 10 mol% C, G 0.125 M 3, 6, 9, 12 20 mol% D, H 0.083 M

Results

Figure 5. Evaluation of reagent and catalyst stoichiometry.

11

Co-source, oxidant, and stoichiometry

Plate Layout

Amount Me3B3O3, K2CO3, and oxidant

Oxidant

Co-source

A-D 2.0 equiv A, E Ag2CO3 1 CoBr2 E-H 4.0 equiv B, F AgOAc 2 CoBr2 + AgPF6 C, G MnF3 3 Cp*CoI2 D, H K2S2O8 4 Cp*CoI2 + AgPF6 5 Cp*Co(CO)I2 6 Cp*Co(CO)I2 + AgPF6 7 IPrCoBr2 8 IPrCoBr2 + AgPF6 9 Cp*Co(PhH)(PF6)2 10 Cp*Co(MeCN)(OTf)2 11 Cp*Co(MeCN)(PF6)2 12 Cp*Co(MeCN)(SbF6)2

Results

Figure 6. Evaluation of Co-catalysts, oxidants and reagents stoichiometry.

Alkyl source, Co-source, and base

Plate Layout

R-[B] Co-source Base

A Me-B(OH)2 1-4 Cp*Co(MeCN)(OTf)2 1, 5, 9 K2CO3 B Me-BF3K 5-8 Cp*Co(MeCN)(PF6)2 2, 6, 10 K3PO4 C Me-Bpin 9-12 Cp*Co(MeCN)(SbF6)2 3, 7, 11 tBuONa D Me-BMIDA 4, 8, 12 KF E Me3B3O3 F Ph3B3O3 G cPr3B3O3 H cPent3B3O3

Results

Figure 7. Evaluation of boron coupling reagents, Co-catalysts, and bases.

12

Base and Co-source

Plate Layout

Co-source Base

A Cp*Co(PhH)(PF6)2 1 Li2CO3 B Cp*Co(MeCN)(OTf)2 2 Na2CO3 C Cp*Co(MeCN)(PF6)2 3 K2CO3 D Cp*Co(MeCN)(SbF6)2 4 Cs2CO3 5 K2PO4 6 tBuONa 7 TMSONa 8 MeONa 9 KOAc 10 KF 11 KHF2 12 “No base”

Results

Figure 8. Evaluation of bases and Co-catalysts.

Temperature, Co-source, and Co-loading with two substrates

Substrate Amount Co-source Co-source Temperature

A-D N-Methylbenzamide (A) A, E 5 mol% 1-5 Cp*Co(PhH)(PF6)2 1 Room temperature E-H Acetanilide (B) B, F 10 mol% 6-10 Cp*Co(MeCN)3(PF6)2 2 40 °C C, G 15 mol% 3 60 °C D, H 20 mol% 4 80 °C 5 100 °C

Results

Figure 9. Evaluation of reaction temperature, catalyst, and catalyst stoichiometry.

13

VI. Competition experiment (Main Text Figure 2b) The reactions were setup using a 96-well Para-dox plate with 1 mL glass vials. All solutions were prepared using dry

degassed 2-methyltetrahydrofuran.

Experimental setup

In a glovebox under nitrogen, the vials were charged with Cp*Co(PhH)(PF6)2 (2.2 mg, 0.004 mmol), K2OC3 (11.1 mg,

0.08 mmol), and Ag2CO3 (22.1 mg, 0.08 mmol) using automated weighing. Using automated liquid dispensing, Substrate

A (0.2 M, 200 μL, 0.04 mmol) and Substrate B (0.2 M, 200 μL, 0.04 mmol) was subsequently added according to

Supplementary Figure 10. Lastly, trimethylboroxine (5.6 μL, 0.04 mmol) was added, the Para-dox plate was closed, and

heated to 60 °C. Aliquots taken out after 140 min and analyzed by LCMS (acidic and basic mobile phase) showed

conversion in most reactions but full conversion in none. See Supplementary Figure 11 for results

Figure 10. Experimental design for competition experiments.

14

Substrate A Substrate B Conversion A Conversion B Conversion A

vs Conversion B

Selectivity

1a 1b 27% 8.3% 3.3 A+B 1a 1e 6.5% 15% 0.4 A+B 1a 1f 48% 0.0% >10 A 1a 1g 58% 0.0% >10 A 1a 1k 2.1% 1.5% 1.4 A+B 1a 1n 58% 0.0% >10 A 1a 1p 51% 0.0% >10 A 1a 1r 56% 1.1% 53 A 1a 1t 43% 0.0% >10 A 1a 1x 28% 2.6% 11 A 1b 1e 2.7% 6.4% 0.4 A+B 1b 1f 7.1% 0.0% >10 A 1b 1g 7.0% 0.0% >10 A 1b 1k 1.4% 1.8% 0.8 A+B 1b 1n 9.5% 0.0% >10 A 1b 1p 6.2% 0.0% >10 A 1b 1r 24% 0.0% >10 A 1b 1t 27% 0.0% >10 A 1b 1x 7.4% 2.6% 2.8 A+B 1e 1f 19% 0.0% >10 A 1e 1g 14% 0.0% >10 A 1e 1k 5.3% 4.1% 1.3 A+B 1e 1n 11% 0.0% >10 A 1e 1p 19% 1.7% 11 A 1e 1r 20% 0.0% >10 A 1e 1t 20% 0.0% >10 A 1e 1x 11% 0.0% >10 A 1f 1g 4.1% 2.0% 2.1 A+B 1f 1k 0.7% 2.0% 0.4 A+B 1f 1n 15% 0.0% >10 A 1f 1p 0.0% 0.0% N/A N/A 1f 1r 11% 16% 0.7 A+B 1f 1t 10% 6.9% 1.4 A+B 1f 1x 0.0% 9.6% <0.1 B 1g 1k 0.0% 1.8% <0.1 B 1g 1n 0.7% 0.0% >10 A 1g 1p 0.0% 0.0% N/A N/A 1g 1r 9.3% 22% 0.4 A+B 1g 1t 7.6% 9.9% 0.8 A+B 1g 1x 0.0% 2.7% <0.1 B 1k 1n 1.4% 0.0% >10 A 1k 1p 1.7% 0.0% >10 A 1k 1r 2.0% 0.0% >10 A 1k 1t 1.5% 0.0% >10 A 1k 1x 2.7% 0.0% >10 A 1n 1p 0.0% 0.0% N/A N/A 1n 1r 0.0% 40% <0.1 B 1n 1t 0.0% 4.3% <0.1 B 1n 1x 0.0% 9.0% <0.1 B 1p 1r 0.0% 0.5% <0.1 B 1p 1t 3.4% 25% 0.1 A+B 1p 1x 0.0% 1.4% <0.1 B 1r 1t 16% 11% 1.5 A+B 1r 1x 8.2% 7.6% 1.1 A+B 1t 1x 7.7% 10% 0.8 A+B

Figure 11. Results from competition experiments. Conversions calculated as product/starting material ratio based on HPLC UV-peaks, not accounting

for UV-response factors. Conversion ratio better then 10:1 was considered full selectivity for one substrate.

15

VII. Compatibility screening (Main Text Figure 3) The reactions were setup using a 96-well Para-dox plate with 1 mL glass vials. All solutions were prepared using dry

degassed 2-methyltetrahydrofurane.

Standard Conditions


0.04 mmol), and Ag2CO3 (11.0 mg, 0.04 mmol) using automated weighing. Using automated liquid dispensing, substrate

in the form of 2-phenylpyridine (0.5 M, 40 μL, 0.02 mmol) or N-methylbenzamide (0.5 M, 40 μL, 0.02 mmol) were

added to the vials, followed by additive according to Supplementary Figure 12 (0.125 M, 160 μL, 0.02 mmol) and

trimethylboroxine (8.5 μL, 0.06 mmol). The Para-dox plate was closed, taken out of the glovebox, and heated to 60 °C.

After 18 hours, the reactions were allowed to cool to room temperature before MeCN (300 μL) were added. The reaction

mixture was stirred for 5 min before aliquots were taken out and analyzed by LCMS (2-phenylpyridine: Acidic mobile

phase; N-methylbenzamide: Basic mobile phase). See Supplementary Figure 13 for results.

100 °C

The reactions were setup according to Standard Conditions only heating to 100 °C for 16 hours.

LSF Condition


0.03 mmol), and Ag2CO3 (8.3 mg, 0.03 mmol) using automated weighing. Using automated liquid dispensing, substrate

in the form of 2-phenylpyridine (0.5 M, 20 μL, 0.01 mmol) or N-methylbenzamide (0.5 M, 20 μL, 0.01 mmol) were

added to the vials, followed by additive according to Supplementary Figure 12 (0.125 M, 80 μL, 0.01 mmol) and

trimethylboroxine (8.5 μL, 0.06 mmol). The Para-dox plate was closed, taken out of the glovebox, and heated to 100 °C.

After 18 hours, the reactions were allowed to cool to room temperature, before MeCN (300 μL) were added. The reaction

mixture was stirred for 5 min before aliquots were taken out and analyzed by LCMS (2-phenylpyridine: Acidic mobile

phase; N-methylbenzamide: Basic mobile phase). See Supplementary Figure 13 for results.

16

Figure 12. Additives used in the compatibility screening.

17

Well

Standard Conditions 100 °C LSF Conditions

SM Me Me2 Tot.

Conv. Rel.

Conv. SM Me Me2

Tot. Conv.

Rel. Conv.

SM Me Me2 Me3 Tot.

Conv. Rel.

Conv.

1A 16% 46% 39% 84% 100% 10% 36% 55% 90% 107% 0% 0% 41% 59% 100% 118% 2A 12% 50% 38% 88% 105% 17% 41% 42% 83% 99% 0% 0% 89% 11% 100% 118% 3A 96% 4% 0% 4% 4% 92% 8% 0% 8% 9% 5% 49% 46% 0% 95% 112% 4A 9% 48% 43% 91% 107% 0% 16% 84% 100% 118% 0% 0% 74% 26% 100% 118% 5A 10% 48% 43% 90% 107% 2% 20% 78% 98% 116% 0% 0% 70% 30% 100% 118% 6A 52% 38% 10% 48% 56% 16% 38% 46% 84% 100% 0% 0% 100% 0% 100% 118% 1B 75% 22% 3% 25% 30% 22% 47% 31% 78% 92% 0% 0% 96% 4% 100% 118% 2B 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 0% 0% 95% 5% 100% 118% 3B 97% 3% 0% 3% 3% 92% 8% 0% 8% 9% 2% 45% 52% 0% 98% 116% 4B 92% 8% 0% 8% 9% 13% 40% 47% 87% 103% 0% 0% 62% 38% 100% 118% 5B 40% 39% 21% 60% 71% 52% 36% 12% 48% 56% 0% 0% 90% 10% 100% 118% 6B 96% 4% 0% 4% 4% 19% 42% 40% 81% 96% 0% 0% 72% 28% 100% 118% 1C 94% 6% 0% 6% 7% 67% 28% 5% 33% 40% 0% 0% 85% 15% 100% 118% 2C 49% 42% 9% 51% 60% 3% 26% 71% 97% 115% 0% 0% 57% 43% 100% 118% 3C 2% 37% 60% 98% 116% 10% 39% 50% 90% 106% 0% 0% 60% 40% 100% 118% 4C 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 86% 14% 0% 0% 14% 16% 5C 28% 43% 29% 72% 86% 53% 36% 11% 47% 55% 0% 0% 84% 16% 100% 118% 6C 2% 28% 70% 98% 116% 12% 39% 49% 88% 104% 0% 0% 61% 39% 100% 118% 1D 6% 38% 56% 94% 111% 12% 39% 49% 88% 104% 0% 0% 70% 30% 100% 118% 2D 4% 29% 67% 96% 114% 18% 42% 40% 82% 97% 0% 0% 58% 42% 100% 118% 3D 52% 29% 19% 48% 56% 14% 38% 48% 86% 102% 0% 0% 100% 0% 100% 118% 4D 24% 31% 44% 76% 90% 68% 27% 5% 32% 38% 0% 0% 68% 32% 100% 118% 5D 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 0% 0% 100% 0% 100% 118% 6D 4% 45% 50% 96% 114% 2% 26% 72% 98% 116% 0% 0% 54% 46% 100% 118% 1E 100% 0% 0% 0% 0% 97% 3% 0% 3% 4% 79% 21% 0% 0% 21% 25% 2E 20% 41% 39% 80% 95% 2% 35% 62% 98% 116% 0% 0% 94% 6% 100% 118% 3E 47% 35% 18% 53% 62% 69% 26% 5% 31% 37% 0% 0% 86% 14% 100% 118% 4E 90% 10% 0% 10% 12% 93% 7% 0% 7% 8% 0% 0% 72% 28% 100% 118% 5E 59% 27% 14% 41% 48% 84% 16% 0% 16% 19% 0% 19% 81% 0% 100% 118% 6E 98% 2% 0% 2% 2% 55% 34% 12% 45% 54% 0% 0% 77% 23% 100% 118% 1F 7% 35% 58% 93% 110% 12% 36% 52% 88% 104% 0% 0% 54% 46% 100% 118% 2F 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 98% 2% 0% 0% 2% 3% 3F 6% 45% 48% 94% 111% 23% 45% 32% 77% 91% 0% 0% 54% 46% 100% 118% 4F 65% 26% 9% 35% 42% 63% 26% 11% 37% 44% 17% 23% 60% 0% 83% 99% 5F 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 96% 4% 0% 0% 4% 5% 6F 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 0% 0% 100% 0% 100% 118% 1G 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 92% 8% 0% 0% 8% 10% 2G 98% 2% 0% 2% 3% 98% 2% 0% 2% 3% 0% 0% 52% 48% 100% 118% 3G 52% 38% 10% 48% 57% 50% 37% 13% 50% 59% 0% 13% 87% 0% 100% 118% 4G 7% 48% 46% 93% 111% 14% 44% 42% 86% 102% 0% 0% 60% 40% 100% 118% 5G 14% 46% 40% 86% 102% 76% 21% 3% 24% 28% 0% 0% 45% 55% 100% 118% 6G 82% 18% 0% 18% 21% 90% 10% 0% 10% 11% 58% 26% 16% 0% 42% 50% 1H 44% 44% 13% 56% 67% 15% 40% 45% 85% 101% 0% 0% 61% 39% 100% 118% 2H 30% 43% 27% 70% 83% 25% 43% 32% 75% 88% 0% 0% 62% 38% 100% 118% 3H 90% 10% 0% 10% 12% 69% 27% 4% 31% 37% 0% 0% 63% 37% 100% 118% 4H 79% 18% 2% 21% 24% 26% 45% 28% 74% 87% 0% 0% 88% 12% 100% 118% 5H 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 0% 6H 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 94% 6% 0% 0% 6% 8%

7A 47% 53% 0% 53% 100% 40% 60% 0% 60% 114% 0% 0% 100% 100% 190% 8A 36% 64% 0% 64% 121% 40% 60% 0% 60% 114% 0% 0% 100% 100% 190% 9A 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 10A 25% 75% 0% 75% 143% 28% 72% 0% 72% 136% 0% 25% 75% 100% 190% 11A 21% 79% 0% 79% 150% 32% 68% 0% 68% 130% 0% 13% 87% 100% 190% 12A 78% 22% 0% 22% 42% 70% 30% 0% 30% 57% 0% 100% 0% 100% 190% 7B 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 0% 100% 0% 100% 190% 8B 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 0% 76% 24% 100% 190% 9B 100% 0% 0% 0% 0% 95% 5% 0% 5% 10% 0% 100% 0% 100% 190% 10B 4% 96% 0% 96% 183% 36% 64% 0% 64% 121% 0% 0% 100% 100% 190% 11B 74% 26% 0% 26% 50% 70% 30% 0% 30% 57% 0% 7% 93% 100% 190% 12B 36% 64% 0% 64% 122% 45% 55% 0% 55% 104% 0% 20% 80% 100% 190% 7C 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 0% 25% 75% 100% 190% 8C 48% 52% 0% 52% 99% 56% 44% 0% 44% 84% 0% 7% 93% 100% 190% 9C 26% 74% 0% 74% 140% 45% 55% 0% 55% 104% 0% 0% 100% 100% 190% 10C 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 11C 100% 0% 0% 0% 0% 88% 12% 0% 12% 22% 0% 16% 84% 100% 190% 12C 28% 72% 0% 72% 136% 40% 60% 0% 60% 114% 0% 0% 100% 100% 190% 7D 100% 0% 0% 0% 0% 32% 68% 0% 68% 129% 0% 0% 100% 100% 190% 8D 12% 88% 0% 88% 167% 39% 61% 0% 61% 116% 0% 0% 100% 100% 190%

18

9D 81% 19% 0% 19% 37% 63% 37% 0% 37% 70% 0% 57% 43% 100% 190% 10D 9% 91% 0% 91% 173% 87% 13% 0% 13% 25% 0% 40% 60% 100% 190% 11D 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 0% 20% 80% 100% 190% 12D 100% 0% 0% 0% 0% 43% 57% 0% 57% 108% 0% 0% 100% 100% 190% 7E 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 52% 48% 0% 48% 91% 8E 56% 44% 0% 44% 84% 37% 63% 0% 63% 119% 0% 26% 74% 100% 190% 9E 100% 0% 0% 0% 0% 81% 19% 0% 19% 35% 11% 50% 39% 89% 169% 10E 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 0% 23% 77% 100% 190% 11E 100% 0% 0% 0% 0% 89% 11% 0% 11% 21% 35% 65% 0% 65% 124% 12E 100% 0% 0% 0% 0% 84% 16% 0% 16% 31% 0% 15% 85% 100% 190% 7F 32% 68% 0% 68% 128% 36% 64% 0% 64% 121% 0% 0% 100% 100% 190% 8F 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 9F 100% 0% 0% 0% 0% 42% 58% 0% 58% 111% 3% 67% 30% 97% 185% 10F 100% 0% 0% 0% 0% 85% 15% 0% 15% 28% 12% 88% 0% 88% 167% 11F 100% 0% 0% 0% 0% 67% 33% 0% 33% 64% 82% 18% 0% 18% 34% 12F 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 5% 55% 40% 95% 180% 7G 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 8G 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 0% 0% 0% 0% 0% 9G 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 87% 13% 0% 13% 25% 10G 39% 61% 0% 61% 115% 66% 34% 0% 34% 64% 0% 0% 100% 100% 190% 11G 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 9% 91% 0% 91% 172% 12G 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 7H 24% 76% 0% 76% 144% 57% 43% 0% 43% 82% 0% 0% 100% 100% 190% 8H 53% 47% 0% 47% 90% 54% 46% 0% 46% 88% 0% 0% 100% 100% 190% 9H 94% 6% 0% 6% 12% 87% 13% 0% 13% 24% 0% 0% 100% 100% 190% 10H 100% 0% 0% 0% 0% 95% 5% 0% 5% 10% 1% 56% 42% 99% 188% 11H 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 12H 100% 0% 0% 0% 0% 100% 0% 0% 0% 0% 100% 0% 0% 0% 0%

Figure 13. Results from compatibility experiment. All ratios based in HPLC UV-peaks using the UV-response factor for the individual compounds.

SM = Starting material, Me = Mono-methylated product, Me2 = Di-methylated product, Me3 = Tri-methylated product, Tot. Conv. = Total conversion

to products (Me + Me2 + Me3), Rel. Conv. = Relative conversion to products versus no additive under standard conditions (Well 1A, Standard

Conditions).

19

VIII. Proposed de novo syntheses (Main Text Table 2 and Figure 4)

Diazepam derivatives 6a1 and 6a2: No known synthetic route. Proposed route based on Diazepam synthesis36.

Strychnine derivative 6b: No known synthetic route. Proposed route based in the Strychnine synthesis by Vanderwal

and co-workers37.

Paclitaxel derivative 6c: The compound was previously described by Himes and coworkers38, applying a semi-synthesis

strategy through an Ojima-type lactam39.

20

Fenofibrate derivatives 6d1, 6d2, and 6d3: Compound 6d1 was previously described by Fournier along with the

synthesis of Fenofibrate40, while 6d2 and 6d3 are unknown. Proposed routes based on Fenofibrate synthesis.

Sulfaphenazole derivatives 6e1 and 6e2: No known synthetic route. Proposed route based on known syntheses of 1-(o-

tolyl)-5-aminopyrazole and Sulfaphenazole41,42.

Warfarin derivative 6f: No known synthetic route. Proposed route base on known syntheses of 5-methyl-4-

hydroxycoumarin and Warfarin43,44.

Metoclopramide derivative 6g: No known synthetic route. Accessing the penta-substituted benzoic acid is challenging

and there is little literature precedence.

Levamisole derivatives 6h1 and 6h2: No known synthetic route. Proposed route based on Levamisole synthesis45.

21

Celecoxib derivatives 6i1 and 6i2: No known synthetic route. Proposed route based on known syntheses of 4-amino-3-

methylbenzenesulfonamide and Celecoxib46,47.

Haloperidol derivative 6j: No known synthetic route. Proposed route based on known syntheses of the key 4-fluoro-2-

methylphenylketone and Haloperidol48.

Apremilast derivative 6k: No known synthetic route. Proposed route based on Apremilast synthesis49. There is however

no precedent for the synthesis of the required di-substituted phthalimide core and selectivity in the proposed nitration will

likely not favor the desired substitution pattern.

Rucaparib derivative 6l: No known synthetic route. Proposed route based on Rucaparib synthesis50.

22

Ivacaftor derivatives 6m1, 6m2, and 6m3: Compound 6m2 was previously described by Vertex Pharmaceuticals51,

while 6m1 and 6m3 are unknown. Proposed routes based on Ivacaftor synthesis and the Vertex Pharmaceuticals strategy

towards 6m252.

6m1:

6m2:

6m3:

Azelastine derivative 6n: No known synthetic route. Proposed route based on Azelastine synthesis53.

23

Atazanavir derivative 6o: No known synthetic route. Proposed route based on Atazanavir synthesis54.

24

IV. PhysChem-, DMPK- and primary activity data (Main Text Figure 5) The products obtained via late stage C–H methylation of marketed pharmaceutically active compounds were subjected to

a range of fundamental drug discovery assays. In Supplementary Figure 20 LogD, polar surface area, solubility, protein

binding, intrinsic clearance (CLint) in rat hepatocytes, and intrinsic clearance in human liver microsomes are shown. For a

selection of compounds, competitive inhibition for 5 important cytochrome P450 enzymes were also tested

(Supplementary Figure 21). Finally, a range of primary pharmacological activity data were also obtained for a selection

of synthesized compounds (Supplementary Figure 22)

LogD increases for some compounds and decreases for others. A slight increase of approximately 0.5 units would

normally be expected for the installation of a methyl group due to its hydrophobic nature. We rationalize the decrease in

LogD, which is observed in a number of cases, with a methyl induced rotation around the aryl-directing group bond,

which in turn makes the polar directing group more accessible. A graphical representation of the observed changes in

LogD for a selection of compounds is shown in Supplementary Figure 14 below.

Figure 14. LogD for a selection of compounds, before and after C–H methylation, light blue: Substrates, dark blue: Products. Error bars (n ≥ 2): ±

Standard error.

Solubility showed no clear trend, but in some instances e.g. Paclitaxel, Apremilast, and Atazanavir a significant increase

is observed. Thus C–H methylation should be considered as a potential strategy for increasing the solubility of poorly

soluble compounds. A plot of the solubility of substrates versus C–H methylated products is shown in Supplementary

Figure 15. Fitting a straight line, this has a slope of 0.9 (R2 = 0.96).

25

Figure 15. Solubility of substrates (x-axis) versus products (y-axis) in μM; dark blue: Mono-methyl, light blue: Di-methyl. Error bars (for n ≥ 2): ±

Standard error.

Human plasma protein binding (fu) showed no clear trend, but C–H methylation does have a significant impact in

some cases, such as for Strychnine and Levamisole. Thus, C–H methylation could be considered if protein binding is

considered as an optimization parameter. A plot of the human plasma protein binding of substrates versus C–H

methylated products is shown in Supplementary Figure 16. Fitting a straight line, this has a slope of 0.8 (R2 = 0.94).

Figure 16. Human plasma protein bunding of substrates (x-axis) versus products (y-axis) as %free; dark blue: Mono-methyl, light blue: Di-methyl.

Error bars (for n ≥ 2): ± Standard error.

26

Intrinsic clearance in rat hepatocytes show substantial changes in some cases. Most significant are for example

Diazepam and Haloperidol, but some less significant decreases are also observed, such as for Apremilast and Ivafactor.

Plotting the intrinsic clearance in rat hepatocytes of substrates versus C–H methylated products (Supplementary Figure

17) and fitting a straight line, this has a slope of 1.8 (R2 = 0.29). This highlights the tendency towards higher clearance

after C–H methylation but also demonstrates that there are exceptions.

Figure 17. Intrinsic clearance in rat hepatocytes of substrates (x-axis) versus products (y-axis) in μL/min/106; dark blue: Mono-methyl, light blue: Di-

methyl. Error bars (for n ≥ 2): ± Standard error.

Intrinsic clearance in human liver microsomes show both increases and decreases upon C–H methylation. In the case

of Diazepam and Atazanavir significant increases are seen. On the other hand, reduced clearance is observed for

Metoclopramide and Paclitaxel. Interestingly, for Ivacaftor methylation in the 2-position (6m1) of the 4-quinolone

fragment increases HLM CLint while installation of a methyl in the 5-position (6m2) reduces HLM CLint. Plotting the

intrinsic clearance in human liver microsomes of substrates versus C–H methylated products (Supplementary Figure 18)

and fitting a straight line, this has a slope of 1.3 (R2 = 0.92).

Figure 18. Intrinsic clearance in human liver microsomes of substrates (x-axis) versus products (y-axis) in μL/min/mg; dark blue: Mono-methyl, light

blue: Di-methyl. Data for 5o/6o was left out for better visualization but was included in straight line fitting (line not shown). Error bars (for n ≥ 2): ±

Standard error.

27

Cytochrome P450 inhibition show significant changes upon C–H methylation. Plotting the cytochrome P450 IC50 of

substrates versus C–H methylated products (Supplementary Figure 19), clearly shows that many compound pairs deviate

from the x=y axis, meaning that a change in CYP inhibition potency has been affected by the C–H methylation. There is

no clear trend toward better or worse CYP inhibition profile after C–H methylation of the marketed drug molecules. It is

remarkable to note that in some instances potent CYP inhibition can be completely removed, shifted to another isoform,

or induced by a simple C–H methylation.

Figure 19. Cytochrome P450 inhibition. Inhibition of 5 cytochrome P450 enzymes by substrates (x-axis) versus products (y-axis), IC50 in μM.

Selected examples. Dark blue: Mono-methyl, light blue: Di-methyl. n = 1.

28

Pharmacological activity shows a reduction in most of the cases. This is unsurprising since this ensemble of substrates

are highly optimized marketed drugs (Supplementary Figure 22). Haloperidol do show increased antagonist activity

towards the dopamine D3 receptor. There are good literature precedents for the potentially beneficial effect of C–H

methylation in medicinal chemistry, but it should obviously not be considered a universal way to increase target potency.

Name Compound LogD Solubility

(μM) Prot. Bind.

(% free) Rat CLint

(μL/min/106) Hu CLint

(μL/min/mg)

Diazepam 5a 2.7 (0.05) 175 (36) 2.0 (1.0) 70 (26) 11 (0.7)

6a1 2.9 (0.05) 85 (1.0) 8.5 (2.7) 105 (1.0) 19 (2.1) 6a2 3.1 (0.05) 147 (15) 9.0 (0.4) 178 (34) 59 (3.5)

Strychnine 5b 1.1 (0.05) 872 (29) 38 (3.5) 12 (4.1) 21 (4.1) 6b 1.4 (0) 818 (44) 21 (1.5) 19 (8.2) 61 (15)

Paclitaxel 5c 3.5 (0.11) 3.0 (0.8) 10 (5.0) 7.0 (0.5) 42 (2.2) 6c 3.9 (0.29) 16 (3.0) *6.9 5.6 (1.4) 23 (0.1)

Fenofibrate 5d >3.8 1.1 (0.1) <0.7 >300 N/A

6d1/6d2 >3.6 <2.4 <0.4 >300 N/A 6d3 *>3.2 *<4.8 *<0.3 N/A N/A

Sulfaphenazole 5e 0.1 (0.01) 794 (217) 0.5 (0.1) <1.4 7.0 (1.7)

6e1 0.3 (0.15) 779 (36) 1.5 (0.1) <1.1 5.4 (1.1) 6e2 *0.4 *729 *1.1 1.2 (0.1) <3.0

Warfarin 5f 0.9 (0.04) 917 (126) 1.3 (0.2) 2.9 (0.2) 4.7 (0.4) 6f 1.9 (0.1) 748 (106) *0.4 5.7 (0.7) 8.0 (0.5)

Metoclopramide 5g 0.7 (0.16) 831 (1.0) 87 (11) 12 (2.8) 5.5 (2.5) 6g -0.0 (0.10) 744 (11) 86 (3.0) 17 (4.9) <3.0

Levamisole

5h 1.2 (0.05) 806 (83) 76 (0.5) 2.7 (1.5) 4.4 (1.0)

6h1 1.6 (0.05) 741 (60) 64 (0.5) 19 (5.1) 5.4 (1.3) 6h2 1.8 (0.05) 858 (49) 55 (0) 61 (15) 8.4 (2.7)

Celecoxib 5i >3.5 2.7 (0.5) <2.4 10 (1.8) 15 (4.0)

6i1 N/A 16 (4.5) <2.9 24 (3.2) 14 (5.5) 6i2 *>3.6 <2.6 <1.4 18 (1.4) 13 (5.3)

Haloperidol 5j 2.8 (0.05) 85 (14) 19 (1.8) 20 (3.4) 12 (1.6) 6j 3.4 (0) 83 (30) *7.0 >300 47 (1.4)

Apremilast 5k 1.7 (0.10) 429 (103) N/A 23 (3.3) 6.6 (3.6) 6k 0.9 (0.15) 638 (59) N/A 11 (3.4) 15 (0.2)

Rucaparib 5l 1.1 (0.04) 784 (36) 34 (4.7) 8.6 (1.2) 3.6 (0.5) 6l *1.6 *646 *19 *5.5 <3.0

Ivacaftor

5m >4.0 2.9 (2.2) <0.3 2.8 (0.2) 44 (3.4) 6m1 >3.2 8.0 (0) <0.3 6.2 (1.1) 86 (13) 6m2 >4.3 1.0 (0.1) *<0.3 <1.0 25 (0.9) 6m3 >4.6 4.0 (2.0) <0.2 <1.0 39 (1.1)

Azelastine 5n 2.4 (0.05) 637 (84) 15 (0.1) 59 (11) 31 (4.3) 6n 3.3 (0.05) 540 (167) 4.6 (1.4) >300 39 (3.4)

Atazanavir 5o 4.0 (0.09) 7.0 (4.0) 11 (1.6) 91 (8.1) 197 (7.7) 6o 4.3 (0.10) 69 (16) *11 53 (17) >300

Figure 20. Selection of PhysChem and DMPK data for late stage methylated compounds and their substrates. All values are measured (n ≥ 2 unless otherwise noted), standard error in parenthesis. The assays were supplied by Discovery Sciences, AstraZeneca. Prot. Bind. = Protein Binding, Rat CLint = Intrinsic clearance in rat hepatocytes (μL/min/106), Hu CLint = Intrinsic clearance in human liver microsomes, N/A = Not available. * n = 1.

29

Name Compound IC50 (μM)

CYP3A4 CYP2D6 CYP2C9 CYP2C19 CYP1A2

Diazepam 5a N/A N/A N/A N/A N/A

6a1 >30 >30 >30 >30 >30 6a2 20.3 >30 >30 >30 >30

Strychnine 5b >30 >30 >30 >30 >30 6b >30 >30 >30 >30 >30

Paclitaxel 5c 15.6 >20 >20 >20 >20 6c 9.1 26.8 >30 >30 >30

Fenofibrate 5d >20 >20 1.2 5.3 >20

6d1/6d2 >30 >30 29.8 >30 >30 6d3 >30 >30 3.8 >30 >30

Sulfaphenazole 5e >30 >30 0.6 25.2 >30

6e1 17.3 >30 2.7 >30 >30 6e2 5.1 >30 >30 >30 >30

Warfarin 5f >30 >30 >10 >30 >30 6f >30 >30 17.0 12.4 >30

Metoclopramide 5g >30 2.5 >30 >30 >30 6g >30 23.5 >30 >30 >30

Levamisole 5h 4.8 5.0 9.6 6.8 1.5

6h1 >30 5.5 >30 >30 >30 6h2 >30 2.8 >30 >30 >30

Celecoxib 5i >10 >10 2.7 >10 >10

6i1 >30 12.2 14.8 18.3 >30 6i2 >30 12.3 12.0 11.8 >30

Haloperidol 5j >20 1.9 >20 >20 >20 6j 25.0 3.6 >30 >30 >30

Apremilast 5k >30 >30 >30 >30 >30 6k >30 >30 >30 >30 >30

Rucaparib 5l >30 >30 7.3 11.6 11.0 6l N/A N/A N/A N/A N/A

Ivacaftor

5m >30 >30 16.0 22.7 >30 6m1 9.6 >30 12.1 19.4 >30 6m2 23.5 >30 >30 >30 >30 6m3 16.4 >30 >30 26.2 >30

Azelastine 5n 3.1 0.9 26.7 16.8 N/A 6n 9.1 2.3 >30 23.6 >30

Atazanavir 5o 1.1 14.3 27.1 6.7 >30 6o 0.7 18.1 >30 >30 >30

Figure 21. Selection of CYP inhibition data for late stage methylated compounds and their substrates. All values are measured (n = 1). The assays were

supplied by Pharmaron Inc. Green: Inactive inhibitor (IC50 > 30 μM), Yellow: Potential moderately active inhibitor (30 μM > IC50 > 10 μM) Red:

Active inhibitor (IC50 < 10 μM).

30

Name Target Assay Assay Supplier* Compound IC50/EC50 (μM) pIC50/pEC50

Strychnine Glycine receptor (antagonist) A 5b 0.022 7.7 6b 0.292 6.5

Metoclopramide

Muscarinic acetylcholine receptor, M1 (agonist) A 5g >100 <4.0 6g >100 <4.0

Dopamine receptor, D2 (antagonist) A 5g 0.19 6.7 6g 2.61 5.6

Paclitaxel Anti-proliferation H358 B 5c 0.004 8.4 6c 0.026 7.6

Haloperidol

Adrenergic receptor, α1a (antagonist) A 5j 0.013 7.9 6j 0.018 7.7

Adrenergic receptor, α2a (antagonist) A 5j >100 <4.0 6j >100 <4.0

Dopamine receptor, D2 (antagonist) A 5j 0.007 8.2 6j 0.013 7.9

Dopamine receptor, D3 (antagonist) A 5j 0.015 7.8 6j <0.010 >8.0

5-Hydroxytryptamine receptor, 5-HT1A (agonist) A 5j >100 <4.0 6j >100 <4.0

5-Hydroxytryptamine receptor, 5-HT2A (agonist) A 5j 0.072 7.1 6j 0.097 7.0

Apremilast Phosphodiesterase 4D2 (inhibitor) A 5k <0.010 >8.0 6k 0.016 7.8

Azelastine Histamine receptor H1 (antagonist) A 5n <0.01 >8.0 6n <0.01 >8.0

Figure 22. Selection of primary activity data for late stage methylated compounds and their substrates. All values are measured (n = 1). *A: CEREP

Laboratories - Eurofins Scientific, B: Discovery Sciences, AstraZeneca.

31

X. Experimental and analytical data for products

2-(o-tolyl)pyridine (3a1) and 2-(2,6-dimethylphenyl)pyridine (3a2) were prepared according to General Procedure A,

using 2-phenylpyridine (72.8 μL, 0.50 mmol) as substrate. Purification by automated flash column chromatography (0-

30% EtOAc in heptane, 25g SiO2). Isolated as a mixture of 3a1 and 3a2 in the mole ratio of 1.0:2.0 (84.6 mg, 95%). See

section XI for 1H NMR spectrum.

The compounds were separated by preparative reverse phase HPLC to give analytically pure samples of the title

compounds as colorless liquids. The spectra matched previously reported data35.

3a1: 1H NMR (500 MHz, CDCl3) δ (ppm) 8.67 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.72 (td, J = 7.7, 1.8 Hz, 1H), 7.32 – 7.45

(m, 2H), 7.16 – 7.32 (m, 4H), 2.34 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 160.2, 149.3, 140.6, 136.2, 135.9,

130.9, 129.7, 128.4, 126.0, 124.2, 121.8, 20.4. HRMS C12H11N; calcd. For (M+H+): 170.0964, found: 170.0964.

3a2: 1H NMR (500 MHz, CDCl3) δ (ppm) 8.74 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.77 (td, J = 7.7, 1.8 Hz, 1H), 7.18 – 7.30

(m, 3H), 7.13 (d, J = 7.6 Hz, 2H), 2.07 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 160.0, 149.8, 140.6, 136.3, 135.8

(2C), 127.9, 127.6 (2C), 124.5, 121.7, 20.3 (2C). HRMS C13H13N; calcd. For (M+H+): 184.1121, found: 184.1124.

2-(2,6-dimethylphenyl)pyridine (3a2) and 2-(2-ethyl-6-methylphenyl)pyridine (3a3) were prepared according to

General Procedure C, with the modification of only heating to 60 °C, using 2-phenylpyridine (72.8 μL, 0.50 mmol) as

substrate. Purification by preparative reverse phase HPLC (20-80% MeCN in NH3 buffer, 260 nm). The relevant

fractions were extracted with CH2Cl2 (3*30 mL), dried over MgSO4, filtered, and concentrated to provide 3a2 (28.8 mg,

31%) and 3a3 (29.1 mg, 30 %) as colorless liquids. The spectra matched previously reported data15.

3a2: See above for analytical data.

3a3: 1H NMR (500 MHz, CDCl3) δ (ppm) 8.72 (d, J = 4.5 Hz, 1H), 7.75 (td, J = 7.7, 1.8 Hz, 1H), 7.22 – 7.3 (m, 3H),

7.15 (d, 7.6 Hz, 1H), 7.11 (d, 7.6 Hz, 1H), 2.36 (q, J = 6.8 Hz, 2H), 2.02 (s, 3H), 1.03 (t, J = 7.6 Hz, 3H). 13C NMR (126

MHz, CDCl3) δ (ppm) 159.9, 149.7, 142.0, 140.1, 136.2, 135.9, 128.2, 127.6, 126.0, 124.7, 121.8, 26.6, 20.4, 15.5.

HRMS C14H15N; calcd. For (M+H+): 198.1277, found: 198.1275.

1-(o-tolyl)-1H-pyrazole (3b1) and 1-(2,6-dimethylphenyl)-1H-pyrazole (3b2) were prepared according to General

Procedure A, using 1-phenylpyrazole (66.1 μL, 0.50 mmol) as substrate. Purification by automated flash column

chromatography (0-30% EtOAc in heptane, 25g SiO2). Isolated as a mixture of 3b1 and 3b2 in the mole ratio of 1.0:1.6

(67.5 mg, 86%). See section XI for 1H NMR spectrum.


compounds as colorless liquids. The spectra for 3b1 matched previously reported data35.

3b1: 1H NMR (600 MHz, CDCl3) δ (ppm) 7.73 (d, J = 1.4 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.25 – 7.35 (m, 4H), 6.44

(t, J = 2.0 Hz, 1H), 2.25 (s, 3H). 13C NMR (151 MHz, CDCl3) δ (ppm) 140.2, 140.0, 133.8, 131.3, 130.5, 128.4, 126.6,

126.2, 106.2, 18.1. HRMS C10H10N2; calcd. For (M+H+): 159.0917, found: 159.0915.

3b2: 1H NMR (600 MHz, CDCl3) δ (ppm) 7.74 (d, J = 1.5 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H),

7.13 (d, J = 7.5 Hz, 2H), 6.45 (t, J = 2.1 Hz, 1H), 2.01 (s, 6H). 13C NMR (151 MHz, CDCl3) δ (ppm) 140.2, 139.5, 136.4

(2C), 130.8, 129.1, 128.3 (2C), 106.0, 17.4 (2C). HRMS C11H12N2; calcd. For (M+H+): 173.1073, found: 173.1069.

2-(o-tolyl)thiazole (3c1) and 2-(2,6-dimethylphenyl)thiazole (3c2) were prepared according to General Procedure A,

using 2-phenylthiazole (87.0 mg, 0.54 mmol) as substrate. Purification by automated flash column chromatography (0-

50% EtOAc in heptane, 25g SiO2). Isolated as a mixture of 1c, 3c1, and 3c2 in the mole ratio of 1.1:1.0:1.4 (86.8 mg,

62% and 29% 1c). See section XI for 1H NMR spectrum.

The compounds were separated by preparative TLC to give analytically pure samples of the title compounds as colorless

liquids. The spectra matched previously reported data55,56.

3c1: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.92 (d, J = 3.3 Hz, 1H), 7.72 (dd, J = 7.6, 1.0 Hz, 1H), 7.40 (d, J = 3.3 Hz,

1H), 7.26 – 7.37 (m, 3H), 2.59 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 168.1, 143.1, 136.7, 133.0, 131.6, 130.2,

129.6, 126.2, 119.6, 21.5. HRMS C10H9NS; calcd. For (M+H+):176.0529, found: 176.0524.

32

3c2: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.94 (d, J = 3.4 Hz, 1H), 7.48 (d, J = 3.4 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H),

7.11 (d, J = 7.7 Hz 2H), 2.14 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 166.8, 142.9, 137.9 (2C), 133.5, 129.4, 127.7

(2C), 120.4, 20.4 (2C). HRMS C11H11NS; calcd. For (M+H+): 190.0685, found: 190.0678.

3-chloro-6-(o-tolyl)pyridazine (3d1) and 3-chloro-6-(2,6-dimethylphenyl)pyridazine (3d2) were prepared according

to General Procedure A, with the modification of using Cp*Co(MeCN)3(PF6)2 (60.7 mg, 0.10 mmol) as catalyst, using 3-

chloro-6-phenylpyridazine (95.3 mg, 0.50 mmol) as substrate. Purification by automated flash column chromatography

(0-40% EtOAc in heptane, 25g SiO2). Isolated as a mixture of 1d, 3d1, and 3d2 in the mole ratio of 2.1:5.6:1.0 (86.3 mg,

65% and 21% 1d). See section XI for 1H NMR spectrum.


compounds as colorless solids. The spectra for 3d2 matched previously reported data57.

3d1: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.52 – 7.6 (m, 2H), 7.27 – 7.42 (m, 4H), 2.37 (s, 3H). 13C NMR (126 MHz,

CDCl3) δ (ppm) 161.4, 155.4, 136.3, 135.9, 131.2, 129.8, 129.7 (2C), 128.1, 126.3, 20.4. HRMS C11H9ClN2; calcd. For

(M+H+): 205.0527, found: 205.0524.

3d2: 1H NMR (500 MHz, CDCl3) δ (ppm) δ 7.60 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H),

7.15 (d, J = 7.6 Hz, 2H), 2.06 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 161.6, 155.7, 136.2 (2C), 136.1, 130.3,

129.3, 128.3, 128.1 (2C), 20.5 (2C). HRMS C12H11ClN2; calcd. For (M+H+): 219.0684, found: 219.0680.

2-(o-tolyl)-4,5-dihydrooxazole (3e1) and 2-(2,6-dimethylphenyl)-4,5-dihydrooxazole (3e2) were prepared according

to General Procedure A, using 2-phenyl-4,5-dihydrooxazole (65.8 μL, 0.50 mmol) as substrate. Purification by

automated flash column chromatography (20-60% EtOAc in heptane, 50 g SiO2). Isolated as two separate fractions, one

containing a mixture of 1e and 3e2 in the mole ratio of 1.8:1.0 (48.9 mg, 22% and 40% 1e), and a second containing pure

3e1 (16.9 mg, 21%), which was isolated as a colorless liquid. See section XI for 1H NMR spectra. Molar ratio of 3e1 and

3e2 was 1.0:1.1 in a total yield of 43%.

Compounds 1e and 3e2 were separated by preparative reverse phase HPLC to give an analytically pure sample of 3e2 as

a colorless liquid. The spectra matched previously reported data35.

3e1: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.79 (d, J = 7.5 Hz, 1H), 7.33 (td, J = 7.5, 1.3 Hz, 1H), 7.19 – 7.25 (m, 2H),

4.38 (t, J = 9.5 Hz, 2H), 4.09 (t, J = 9.5 Hz, 2H), 2.59 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 165.2, 138.8, 131.3,

130.6, 129.9, 127.3, 125.7, 66.9, 55.5, 21.9. HRMS C10H11NO; calcd. For (M+H+): 162.0913, found: 162.0914.

3e2: 1H NMR (600 MHz, CDCl3) δ (ppm) 7.18 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 2H), 4.41 (t, J = 9.6 Hz, 2H),

4.10 (t, J = 9.6 Hz, 2H), 2.32 (s, 6H). 13C NMR (151 MHz, CDCl3) δ (ppm) 165.0, 137.1 (2C), 129.4, 129.1, 127.5 (2C),

67.3, 55.4, 19.8 (2C). HRMS C11H13NO; calcd. For (M+H+): 176.1070, found:176.1064.

N,2-dimethylbenzamide (3f1) and N,2,6-trimethylbenzamide (3f2) were prepared according to General Procedure A,

using N-methylbenzamide (67.6 mg, 0.50 mmol) as substrate. Purification by automated flash column chromatography

(0-100% EtOAc in heptane, 25g SiO2). Isolated as a mixture of 3f1 and 3f2 in the mole ratio of 6.0:1.0 (75.2 mg, 99%).

See section XI for 1H NMR spectrum.


compounds as off-white solids. The spectra matched previously reported data35.

3f1: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.22 – 7.28 (m, 2H), 7.15 (d, J = 7.5 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.22 (br

s, 1H), 2.87 (d, J = 4.9 Hz, 3H), 2.35 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 170.9, 136.5, 135.9, 130.9, 129.7,

126.7, 125.6, 26.5, 19.7. HRMS C9H11NO; calcd. For (M+H+): 150.0913, found: 150.0906.

3f2: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.14 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 7.6 Hz, 2H), 5.65 (br s, 1H), 3.01 (d, J =

4.9 Hz, 3H), 2.30 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 171.3, 137.8, 134.4 (2C), 128.8, 127.6 (2C), 26.5, 19.3

(2C). HRMS C10H13NO; calcd. For (M+H+): 164.1070, found: 164.1066.

33

N-(tert-butyl)-2-methylbenzamide (3g1) and N-(tert-butyl)-2,6-dimethylbenzamide (3g2) were prepared according to

General Procedure A, using N-(tert-butyl)benzamide (88.6 mg, 0.50 mmol) as substrate. Purification by automated flash

column chromatography (0-50% EtOAc in heptane, 25g SiO2). Isolated as a mixture of 3g1 and 3g2 in the mole ratio of

3.4:1.0 (96.1 mg, 99%). See section XI for 1H NMR spectrum.


compounds as colorless solids. The spectra for 3g1 matched previously reported data58.

3g1: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.22 – 7.31 (m, 2H), 7.12 – 7.19 (m, 2H), 5.61 (br s, 1H), 2.41 (s, 3H), 1.44

(s, 9H). 13C NMR (126 MHz, CDCl3) δ (ppm) 169.8, 138.0, 135.5, 130.8, 129.4, 126.5, 125.7, 51.8, 28.9 (3C), 19.6.

HRMS C12H17NO; calcd. For (M+H+): 192.1383, found: 192.1376.

3g2: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.13 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 2H), 5.46 (br s, 1H), 2.34 (s, 6H),

1.47 (s, 9H). 13C NMR (126 MHz, CDCl3) δ (ppm) 169.6, 138.7, 134.1 (2C), 128.5, 127.5 (2C), 51.9, 29.0 (3C), 19.1

(2C). HRMS C13H19NO; calcd. For (M+H+): 206.1539, found: 206.1533.

8-methyl-3,4-dihydroisoquinolin-1(2H)-one (3h) was prepared according to General Procedure A, using 3,4-

dihydroisoquinolin-1(2H)-one (73.6 mg, 0.50 mmol) as substrate. Purification by automated flash column

chromatography (0-10% MeOH in EtOAc, 25g SiO2). Isolated as a mixture of 1h and 3h in the mole ratio of 1.0:3.1

(77.3 mg, 74% and 24% 1h). See section XI for 1H NMR spectrum.

The compounds were separated by preparative reverse phase HPLC to give an analytically pure sample of the title

compound as a colorless solid. The spectra matched previously reported data59. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.28 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.97 (br

s, 1H), 3.46 (td, J = 6.4, 3.4 Hz, 2H), 2.94 (t, J = 6.4 Hz, 2H), 2.71 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 167.3,

141.0, 140.3, 131.1, 130.9, 127.5, 125.3, 39.9, 30.1, 22.3. HRMS C10H11NO; calcd. For (M+H+): 162.0913, found:

162.0910.

9-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (3i) was prepared according to General Procedure A, with the

modification of using 20 mol% Cp*Co(PhH)(PF6)2 (56.2 mg, 0.1 mmol), using 2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-

one (80.6 mg, 0.50 mmol) as substrate. Purification by automated flash column chromatography (0-100% EtOAc in

heptane, 25g SiO2). Isolated as a mixture of 1i and 3i in the mole ratio of 1.0:1.7 (71.9 mg, 53% and 31% 1i). See section

XI for 1H NMR spectrum.


compound as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 8.05 (br s, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.04 (d, J =

7.4 Hz, 1H), 2.83 (br s, 2H), 2.65 (t, J = 7.0 Hz, 2H), 2.32 (s, 3H), 1.77 (br s, 2H). 13C NMR (126 MHz, CDCl3) δ (ppm)

170.8, 137.0, 136.1, 134.7, 129.4, 128.9, 125.8, 38.0, 30.0, 29.7, 19.7. HRMS C11H13NO; calcd. For (M+H+): 176.1070,

found: 176.1073.

N,3-dimethylthiophene-2-carboxamide (3j1) and N,3,5-trimethylthiophene-2-carboxamide (3j2) were prepared

according to General Procedure A, using N-methylthiophene-2-carboxamide (70.6 mg, 0.50 mmol) as substrate.

Purification by automated flash column chromatography (0-70% EtOAc in heptane, 25g SiO2). Isolated as a mixture of

3j1 and 3j2 in the mole ratio of 11.0:1.0 (35.2 mg, 45%). See section XI for 1H NMR spectrum.


compounds as colorless solids. The spectra for 3j1 matched previously reported data35.

3j1: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.23 (d, J = 5.0 Hz, 1H), 6.86 (d, J = 5.0 Hz, 1H), 5.88 (br s, 1H), 2.95 (d, J =

4.8 Hz, 3H), 2.50 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 164.0, 141.0, 132.0, 131.0, 126.3, 26.8, 15.8. HRMS

C7H9NOS; calcd. For (M+H+): 156.0478, found: 156.0476.

3j2: 1H NMR (500 MHz, CDCl3) δ (ppm) 6.56 (s, 1H), 5.68 (br s, 1H), 2.95 (d, J = 4.8 Hz, 3H), 2.44 (s, 3H), 2.43 (d, J =

0.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 164.0, 141.6, 141.2, 130.8, 128.4, 26.8, 15.9, 15.5. HRMS

C8H11NOS; calcd. For (M+H+): 170.0634, found: 170.0634.

34

2,5-dimethylbenzamide (3k) was prepared according to General Procedure A, with the modification of using 20 mol%

Cp*Co(PhH)(PF6)2 (56.2 mg, 0.1 mmol), using 3-methylbenzamide (67.6 mg, 0.50 mmol) as substrate. Purification by

automated flash column chromatography (0-10% MeOH in EtOAc, 25g SiO2). Isolated as a mixture of 1k and 3k in the

mole ratio of 1.0:2.7 (67.2 mg, 67% and 25% 1k). See section XI for 1H NMR spectrum.


compound as a colorless solid. The spectra matched previously reported data60. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.27 (s, 1H), 7.09 – 7.17 (m, 2H), 5.86 (br s, 1H), 5.75 (br s, 1H) 2.45 (s, 3H), 2.33

(s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 172.3, 135.5, 135.1, 133.2, 131.3, 131.2, 127.7, 21.0, 19.7. HRMS

C9H11NO; calcd. For (M+H+): 150.0913, found: 150.0916.

2-(2-hydroxyethoxy)-6-methylbenzamide (3l) was prepared according to General Procedure A, with the modification

of using 20 mol% Cp*Co(PhH)(PF6)2 (56.2 mg, 0.1 mmol), using 2-(2-hydroxyethoxy)benzamide (90.6 mg, 0.50 mmol)

as substrate. Purification by automated flash column chromatography (0-15% MeOH in EtOAc, 25g SiO2). Isolated as a

mixture of 1l and 3l in the mole ratio of 1.0:2.7 (88.5 mg, 67% and 25% 1l). See section XI for 1H NMR spectrum.


compound as a colorless solid. 1H NMR (500 MHz, CD3CN) δ (ppm) 7.22 (t, J = 8.0 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.56

(br s, 1H), 6.24 (br s, 1H), 4.06 – 4.12 (m, 2H), 3.68 – 3.75 (m, 2H), 3.44 (t, J = 6.1 Hz, 1H), 2.29 (s, 3H). 13C NMR

(126 MHz, CD3CN) δ (ppm) 171.0, 156.4, 137.2, 130.6, 128.7, 123.9, 112.3, 72.3, 61.3, 19.4. HRMS C10H13NO3; calcd.

For (M+H+): 196.0968, found: 196.0966.

6-chloro-2-methoxy-3-methylisonicotinamide (3m) was prepared according to General Procedure A, with the

modification of using Cp*Co(MeCN)3(PF6)2 (60.7 mg, 0.10 mmol) as catalyst and heating to 100 °C, using 2-chloro-6-

methoxyisonicotinamide (93.3 mg, 0.50 mmol) as substrate. Purification by automated flash column chromatography (0-

100% EtOAc in heptane, 25g SiO2). Isolated as a mixture of 1m and 3m in the mole ratio of 1.3:1.0 (52.4 mg, 24% and

31% 1m). See section XI for 1H NMR spectrum.


compound as a colorless solid. 1H NMR (600 MHz, CD3OD) δ (ppm) 6.94 (s, 1H), 3.95 (s, 3H), 2.19 (s, 3H). 13C NMR (151 MHz, CD3OD) δ (ppm)

171.8, 163.7, 149.5, 146.5, 117.4, 114.9, 54.9, 12.1. HRMS C8H9ClN2O2; calcd. For (M+H+): 201.0425, found:

201.0416.

N,N,2-trimethylbenzamide (3n) was prepared according to General Procedure A, with the modification of using 20

mol% Cp*Co(PhH)(PF6)2 (56.2 mg, 0.1 mmol), using N,N-dimethylbenzamide (74.6 mg, 0.50 mmol) as substrate.


1n and 3n in the mole ratio of 1.0:7.5 (74.7 mg, 82% and 11% 1n). See section XI for 1H NMR spectrum.


compound as a colorless liquid. The spectra matched previously reported data61. 1H NMR (500 MHz, CD3CN) δ (ppm) 7.19 – 7.32 (m, 3H), 7.13 (dd, J = 7.5, 1.1 Hz, 1H), 3.03 (s, 3H), 2.75 (s, 3H),

2.22 (s, 3H). 13C NMR (126 MHz, CD3CN) δ (ppm) 171.6, 138.4, 134.9, 131.1, 129.4, 126.7, 126.6, 38.5, 34.4, 18.9.

HRMS C10H13NO; calcd. For (M+H+): 164.1070, found: 164.1073.

35

(4-bromo-2-methylphenyl)(pyrrolidin-1-yl)methanone (3o) was prepared according to General Procedure A, with the

modification of using 20 mol% Cp*Co(PhH)(PF6)2 (56.2 mg, 0.1 mmol), using (4-bromophenyl)(pyrrolidin-1-

yl)methanone (127.1 mg, 0.50 mmol) as substrate. Purification by automated flash column chromatography (35-75%

EtOAc in heptane, 50g SiO2). Isolated as a mixture of 1o and 3o in the mole ratio of 1.0:1.0 (123.3 mg, 47% and 47%

1o). See section XI for 1H NMR spectrum.


compound as a colorless liquid. The spectra matched previously reported data62. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.38 (d, J = 1.3 Hz, 1H), 7.34 (dd, J = 8.1, 1.9 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H),

3.64 (t, J = 7.0 Hz, 2H), 3.12 (t, J = 6.7 Hz, 2H), 2.29 (s, 3H), 1.96 (p, J = 6.6 Hz, 2H), 1.87 (p, J = 6.6 Hz, 2H). 13C

NMR (126 MHz, CDCl3) δ (ppm) 169.0, 136.9, 136.4, 133.5, 129.2, 127.3, 122.8, 48.5, 45.5, 26.2, 24.7, 19.0. HRMS

C12H14BrNO; calcd. For (M+H+): 268.0332, found: 268.0346.

N-(o-tolyl)acetamide (3p) was prepared according to General Procedure A, using N-phenylacetamid (67.6 mg, 0.50

mmol) as substrate. Purification by automated flash column chromatography (30-80% EtOAc in heptane, 50 g SiO2).

Isolated as a mixture a colorless solid (35.3 mg, 47%). The spectra matched previously reported data63. The compounds

were obtained with approximately 90% purity. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.72 (d, J = 7.9 Hz, 1H), 7.15 – 7.23 (m, 2H), 7.10 (br s, 1H), 7.08 (t, J = 7.4 Hz,

1H), 2.25 (s, 3H), 2.19 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 168.6, 135.7, 130.6, 129.6, 126.8, 125.5, 123.7,

24.4, 17.9. HRMS C9H11NO; calcd. For (M+H+): 150.0913, found: 150.0909.

1-(4-(dimethylamino)-2-methylphenyl)ethan-1-one (3q1) and 1-(4-(dimethylamino)-2,6-dimethylphenyl)ethan-1-

one (3q2) were prepared according to General Procedure A, using 1-(4-(dimethylamino)phenyl)ethan-1-one (81.6 mg,

0.50 mmol) as substrate. Purification by automated flash column chromatography (0-40% EtOAc in heptane, 25g SiO2).

Isolated as a mixture of 1q, 3q1 and 3q2 in the mole ratio of 1.0:4.2:3.1 (85.1 mg, 83% and 11% 1q). See section XI for 1H NMR spectrum.


compounds as slightly orange liquids.

3q1: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.73 (d, J = 8.8 Hz, 1H), 6.49 (dd, J = 8.8, 2.7 Hz, 1H), 6.46 (d, J = 2.6 Hz,

1H), 3.02 (s, 6H), 2.59 (s, 3H), 2.51 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 198.5, 152.4, 142.3, 133.2, 124.7,

114.6, 108.1, 40.0 (2C), 28.7, 23.6. HRMS C11H15NO; calcd. For (M+H+):178.1226, found: 178.1227.

3q2: 1H NMR (500 MHz, CDCl3) δ (ppm) 6.35 (s, 2H), 2.94 (s, 6H), 2.45 (s, 3H), 2.26 (s, 6H). 13C NMR (126 MHz,

CDCl3) δ (ppm) 208.1, 150.6, 134.6 (2C), 131.3, 111.7 (2C), 40.4 (2C), 32.7, 20.5 (2C). HRMS C12H17NO; calcd. For

(M+H+): 192.1383, found: 192.1375.

5-methyl-2-phenyl-4H-chromen-4-one (3r) was prepared according to General Procedure A, using 2-phenyl-4H-

chromen-4-one (111.1 mg, 0.50 mmol) as substrate. Purification by automated flash column chromatography (0-40%

EtOAc in heptane, 25g SiO2). Isolated as a yellow solid (58.4 mg, 49%). The spectra matched previously reported data28. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.88 (dd, J = 7.3, 2.0 Hz, 2H), 7.45 – 7.52 (m, 4H), 7.37 (d, J = 8.3 Hz, 1H), 7.11

(d, J = 7.3 Hz, 1H), 6.71 (s, 1H), 2.88 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 180.6, 161.6, 157.8, 141.1, 132.7,

131.7, 131.4, 129.0 (2C), 127.8, 126.2 (2C), 122.4, 116.1, 108.9, 22.8. HRMS C16H12O2; calcd. For (M+H+): 237.0910,

found: 237.0909.

36

4-(dimethylamino)-2-methoxy-6-methylbenzaldehyde (3s) was prepared according to General Procedure A, using 4-

(dimethylamino)-2-methoxybenzaldehyde (89.6 mg, 0.50 mmol) as substrate. Purification by automated flash column

chromatography (0-40% EtOAc in heptane, 25g SiO2). Isolated as a pale orange solid (63.6 mg, 66%). 1H NMR (500 MHz, CDCl3) δ (ppm) 10.36 (s, 1H), 6.03 (d, J = 2.1 Hz, 1H), 5.93 (d, J = 2.3 Hz, 1H), 3.85 (s, 3H), 3.04

(s, 6H), 2.56 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 189.4, 165.5, 154.6, 144.1, 113.2, 107.3, 91.5, 55.5, 40.1

(2C), 22.8. HRMS C11H15NO2; calcd. For (M+H+): 194.1176, found: 194.1174.

6-methoxy-8-methylquinoline (3t) was prepared according to General Procedure A, using 6-methoxyquinoline N-oxide

(87.6 mg, 0.50 mmol) as substrate. The quinoline N-oxide was reduced under the reaction conditions. Purification by

automated flash column chromatography (0-60% EtOAc in heptane, 25g SiO2). Isolated as a slightly orange liquid (41.9

mg, 48%). The spectra matched previously reported data64. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.78 (d, J = 3.3 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.33 (dd, J = 8.2, 4.2 Hz, 1H),

7.23 (s, 1H), 6.90 (d, J = 2.4 Hz, 1H), 3.90 (s, 3H), 2.77 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 157.4, 146.9,

143.9, 138.9, 135.2, 129.5, 122.3, 121.3, 103.2, 55.5, 18.2. HRMS C11H11NO; calcd. For (M+H+): 174.0913, found:

174.0909.

4-chloro-8-methylnaphthalen-1-ol (3u) was prepared according to General Procedure A, with the modification of using

20 mol% Cp*Co(PhH)(PF6)2 (56.2 mg, 0.1 mmol), using 4-chloronaphthalen-1-ol (89.3 mg, 0.50 mmol) as substrate. The

crude reaction mixture was poured into 2 M HCl (30 mL) and extracted with CH2Cl2 (4*30 mL). The combined organic

phases were dried over MgSO4, filtered, and concentrated, before purification by automated flash column

chromatography (0-40% EtOAc in heptane, 25g SiO2). Isolated as a brown solid (40.5 mg, 42%). 1H NMR (500 MHz, CDCl3) δ (ppm) 8.10 (d, J = 8.6 Hz, 1H), 7.44 (dd, J = 8.5, 7.1 Hz 1H), 7.35 (d, J = 8.1 Hz, 1H),

7.27 (d, J = 7.1 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 5.29 (br s, 1H), 2.95 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm)

153.2, 135.7, 133.1, 129.2, 127.3, 125.8, 125.0, 124.0, 122.9, 110.0, 24.9. HRMS C11H9ClO; calcd. For (M-H+):

191.0269, found: 191.0264.

8-methylnaphthalen-1-amine (3v) was prepared according to General Procedure A, with the modification of using 20

mol% Cp*Co(PhH)(PF6)2 (56.2 mg, 0.1 mmol), using naphthalen-1-amine (71.6 mg, 0.50 mmol) as substrate.


1v and 3v in the mole ratio of 1.0:1.0 (48.0 mg, 32% and 32% 1v). See section XI for 1H NMR spectrum.


compound as a brown solid. The spectra matched previously reported data65. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.61 (d, J = 8.2 Hz, 1H), 7.24 – 7.30 (m, 2H), 7.21 (t, J = 8.0 Hz, 1H), 7.13 (d, J =

7.0 Hz, 1H), 6.69 (dd, J = 7.3, 1.3 Hz, 1H), 4.34 (br s, 2H), 3.02 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 144.9,

136.5, 133.7, 128.3, 127.6, 126.1, 125.4, 124.3, 120.1, 112.0, 25.3. HRMS C11H11N; calcd. For (M+H+): 158.0964,

found: 158.0964.

8-ethylquinoline (3w) was prepared according to General Procedure A, with the modification of using 20 mol%

Cp*Co(PhH)(PF6)2 (56.2 mg, 0.1 mmol), using 8-methylquinoline (71.6 mg, 0.50 mmol) as substrate. Purification by

automated flash column chromatography (0-50% EtOAc in heptane, 25g SiO2). Isolated as a mixture of 1w and 3w in the

mole ratio of 1.0:1.1 (61.2 mg, 43% and 39% 1w). See section XI for 1H NMR spectrum.


compound as a colorless liquid. The spectra matched previously reported data66. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.95 (dd, J = 4.2, 1.8 Hz, 1H), 8.14 (dd, J = 8.2, 1.8 Hz, 1H), 7.67 (dd, J = 8.1, 1.2

Hz, 1H), 7.58 (d, J = 7.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 8.2, 4.2 Hz, 1H), 3.32 (q, J = 7.5 Hz, 2H), 1.40

37

(t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 149.4, 146.9, 143.0, 136.5, 128.5, 128.0, 126.6, 126.0, 120.9,

24.7, 15.2. HRMS C11H11N; calcd. For (M+H+): 158.0964, found: 158.0972.

N-(3-methyl-4-(pyridin-2-yl)phenyl)acetamide (3x1) and N-(3,5-dimethyl-4-(pyridin-2-yl)phenyl)acetamide (3x2)

were prepared according to General Procedure A, using N-(4-(pyridin-2-yl)phenyl)acetamide (106 mg, 0.50 mmol) as

substrate. Purification by automated flash column chromatography (50-100% EtOAc in heptane, 25g SiO2). Isolated as a

mixture of 3x1 and 3x2 in the mole ratio of 1.0:0.95 (107.4 mg, 92%). See section XI for 1H NMR spectrum.


compounds as colorless solids.

3x1: 1H NMR (500 MHz, C6D6) δ (ppm). 8.56 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.55 (dd, J = 8.0, 1.0 Hz 1H), 7.43 (d, J =

8.5 Hz 1H), 7.40 (s, 1H), 7.09 (td, J = 7.6, 1.9 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.74 (br s, 1H), 6.65 (ddd, J = 7.4, 4.8,

1.2 Hz, 1H), 2.41 (s, 3H), 1.59 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 167.5, 160.2, 149.3, 139.1, 137.2, 136.4,

135.9, 130.9, 124.1, 121.9, 121.3, 117.3, 24.2, 21.0. HRMS C14H14N2O; calcd. For (M+H+): 227.1179, found: 227.1177.

3x2: 1H NMR (500 MHz, C6D6) δ (ppm) 8.52 (ddd, J = 4.9, 1.7, 0.9 Hz, 1H), 7.63 (br s, 1H), 7.34 (s, 2H), 7.09 (td, J =

8.0, 2.0 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.65 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 2.01 (s, 6H), 1.74 (s, 3H). 13C NMR (126

MHz, CDCl3) δ (ppm) 167.8, 160.3, 149.7, 138.6, 136.6, 136.5 (2C), 136.1, 125.1, 121.6, 119.5 (2C), 24.2, 20.6 (2C).

HRMS C15H16N2O; calcd. For (M+H+): 241.1335, found: 241.1336.

5-acetyl-2-methylbenzamide (3y) was prepared according to General Procedure A, using 3-acetylbenzamide (81.6 mg,

0.50 mmol) as substrate. Purification by automated flash column chromatography (0-30% EtOAc in heptane, 25g SiO2).

Isolated as a mixture of 1y and 3y in the mole ratio of 0.1:1.0 (79.7 mg, 82% and 8% 1y). See section XI for 1H NMR

spectrum


compound as colorless solid. 1H NMR (500 MHz, CDCl3) δ (ppm). 7.92 (d, J = 1.8 Hz, 1H), 7.89 (dd, J = 8.0, 2.0 Hz, 1H), 7.87 (br s, 1H), 7.50 (br s,

1H), 7.39 (d, J = 7.9 Hz, 1H), 2.58 (s, 3H), 2.43 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 197.2, 170.3, 141.1,

137.2, 134.3, 131.0, 128.8, 126.9, 26.7, 19.8. HRMS C10H11NO2; calcd. For (M+H+): 178.0863, found: 178.0861.

2-methyl-N-phenylbenzamide (3z1) and 2,6-dimethyl-N-phenylbenzamide (3z2) were prepared according to General

Procedure A, using N-phenylbenzamide (98.6 mg, 0.50 mmol) as substrate. Purification by automated flash column

chromatography (0-60% EtOAc in heptane, 25g SiO2). Isolated as a mixture of 1z, 3z1 and 3z2 in the mole ratio of

2.0:2.6:1.0 (104.7 mg, 64% and 36% 1z). See section XI for 1H NMR spectrum.


compounds as colorless solids. The spectra matched previously reported data35,67.

3z1: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.71 (br s, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.31 – 7.38

(m, 3H), 7.19 – 7.27 (m, 2H), 7.15 (t, J = 7.4 Hz, 1H), 2.47 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 168.3, 138.1,

136.5, 136.4, 131.3, 130.3, 129.2 (2C), 126.7, 126.0, 124.6, 120.0 (2C), 19.9. HRMS C14H13NO; calcd. For (M+H+):

212.1070, found: 212.1061.

3z2: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.62 (d, J = 8.3 Hz, 2H), 7.41 (br s, 1H), 7.38 (t, J = 8.0 Hz, 2H), 7.21 (t, J =

7.6 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 7.6 Hz, 2H), 2.39 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 168.7,

137.9, 137.8, 134.5 (2C), 129.3 (2C), 129.2, 127.8 (2C), 124.8, 120.0 (2C), 19.4 (2C). HRMS C15H15NO; calcd. For

(M+H+): 226.1226, found: 226.1226.

38

7-chloro-1-methyl-5-(o-tolyl)-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (6a1) and 7-chloro-5-(2,6-

dimethylphenyl)-1-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (6a2) were prepared according to General

Procedure B, using 7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (Diazepam) (142 mg, 0.50

mmol) as substrate. Purification by preparative reverse phase HPLC (20-60% MeCN in AcOH buffer, 254 nm) to give

6a1 (46.0 mg, 31%) and 6a2 (85.8 mg, 55%) as colorless solids.

6a1: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.47 (dd, J = 8.8, 2.5 Hz, 1H), 7.32 – 7.38 (m, 2H), 7.28 (d, J = 9.0 Hz, 2H),

7.19 (d, J = 7.9 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 4.86 (d, J = 11.0 Hz, 1H), 3.81 (d, J = 10.6 Hz, 1H), 3.44 (s, 3H), 1.98

(s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 171.0, 169.9, 141.7, 138.7, 136.3, 131.9, 131.6, 131.0, 129.9, 129.8,

129.7, 129.0, 126.1, 122.7, 56.8, 34.9, 20.0. HRMS C17H15ClN2O; calcd. For (M+H+): 299.0946, found: 299.0950.

6a2: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.46 (dd, J = 8.8, 2.5 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 7.21 (t, J = 7.5 Hz,

1H), 7.17 (br s, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.98 (br s, 1H), 4.88 (s, 1H), 3.90 (s, 1H), 3.44 (s, 3H), 2.41 (br s, 3H),

1.78 (br s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 170.7, 169.6, 141.6, 138.6, 135.6 (2C), 131.5, 131.4, 129.8, 128.9,

128.3, 128.1 (2C), 122.8, 56.6, 34.9, 20.1, 19.1. HRMS C18H17ClN2O; calcd. For (M+H+):313.1102, found: 313.1105.

(4aR,4a1R,5aS,8aR,8a1S,15aS)-12-methyl-2,4a,4a1,5,5a,7,8,8a1,15,15a-decahydro-14H-4,6-methanoindolo[3,2,1-

ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one (6b) was prepared according to General Procedure B, using

(4aR,4a1R,5aS,8aR,8a1S,15aS)-2,4a,4a1,5,5a,7,8,8a1,15,15a-decahydro-14H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-

de]pyrrolo[2,3-h]quinolin-14-one (Strychnine) (167 mg, 0.50 mmol) as substrate. Purification by preparative reverse

phase HPLC (0-45% MeCN in TFA buffer, 254 nm) to give 6b (48.1 mg, 28%) as a colorless solid. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.11 (d, J = 7.4 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 7.1 Hz, 1H), 5.92 (t,

J = 6.1 Hz, 1H), 4.27 – 4.32 (m, 1H), 4.16 (dd, J = 13.8, 7.0 Hz, 1H), 4.04 – 4.10 (m, 1H), 4.02 (br s, 1H), 3.95 (d, J =

10.4 Hz, 1H), 3.71 (d, J = 14.7 Hz, 1H), 3.13 – 3.19 (m, 2H), 3.09 (dd, J = 14.9, 8.9 Hz, 1H), 2.81 – 2.90 (m, 1H), 2.74

(d, J = 14.8 Hz, 1H), 2.70 (dd, J = 14.9, 4.4 Hz, 1H), 2.40 (s, 3H), 2.36 (dt, J = 14.3, 4.3 Hz, 1H), 1.70 – 1.79 (m, 2H),

1.51 (d, J = 14.3 Hz, 1H), 1.20 (dt, J = 10.4, 3.2 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ (ppm) 169.7, 140.6, 140.5,

134.0, 132.2, 127.9, 127.6, 125.1, 119.2, 78.0, 64.7, 60.9, 59.8, 52.7, 52.2, 50.0, 49.1, 44.4, 43.5, 32.1, 26.8, 22.8.

HRMS C22H24N2O2; calcd. For (M+H+): 349.1911, found: 349.1913.

(2aR,4S,4aS,6R,9S,11S,12S,12bS)-12-(benzoyloxy)-4,11-dihydroxy-9-(((2R,3S)-2-hydroxy-3-(2-methylbenzamido)-

3-phenylpropanoyl)oxy)-4a,8,13,13-tetramethyl-5-oxo-3,4,4a,5,6,9,10,11,12,12a-decahydro-1H-7,11-

methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b(2aH)-diyl diacetate (6c) was prepared according to General Procedure

B, but at half scale and using 6.0 equiv. trimethylboroxine (212 μL, 1.50 mmol), using (2aR,4S,4aS,6R,9S,11S,12S,12bS)-

9-(((2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-

5-oxo-3,4,4a,5,6,9,10,11,12,12a-decahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b(2aH)-diyl diacetate

(Paclitaxel) (213 mg, 0.25 mmol) as substrate. Purification by preparative reverse phase HPLC (25-75% MeCN in AcOH

buffer, 230 nm) to give 6c (70.3 mg, 32%) as a colorless solid. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.09 (d, J = 7.3 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.40 – 7.53 (m, 6H), 7.26 – 7.39

(m, 3H), 7.17 (d, J = 7.5 Hz, 2H), 6.64 (d, J = 9.1 Hz, 1H), 6.29 (s, 1H), 6.24 (t, J = 8.7 Hz, 1H), 5.73 (dd, J = 9.1, 1.9

Hz, 1H), 5.67 (d, J = 7.0 Hz, 1H), 4.92 (d, J = 8.3 Hz, 1H), 4.74 (s, 1H), 4.39 (dd, J = 10.7, 6.8 Hz, 1H), 4.28 (d, J = 8.5

Hz, 1H), 4.18 (d, J = 8.5 Hz, 1H), 3.79 (d, J = 6.9 Hz, 1H), 3.62 (br s, 1H), 2.47 – 2.57 (m, 2H), 2.39 (d, J = 9.1 Hz, 2H),

2.35 (s, 6H), 2.23 (s, 3H), 2.06 (br s, 1H), 1.84 – 1.90 (m, 1H), 1.83 (s, 3H), 1.67 (s, 3H) 1.24 (s, 3H), 1.14 (s, 3H). 13C

NMR (126 MHz, CDCl3) δ (ppm) 203.8, 173.2, 171.4, 170.3, 170.0, 167.0, 142.1, 138.1, 136.4, 135.5, 133.8, 133.4,

131.3, 130.5, 130.3 (2C), 129.3, 129.2 (2C), 128.8 (2C), 128.5, 127.2 (2C), 126.8, 126.0, 84.5, 81.3, 78.9, 76.6, 75.7,

75.1, 73.0, 72.8, 72.2, 58.7, 55.0, 45.7, 43.4, 35.8, 35.7, 26.9, 22.8, 22.0, 21.0, 19.8, 14.9, 9.7. HRMS C48H53NO14; calcd.

For (M+H+): 868.3539, found: 868.3541.

39

isopropyl 2-(4-(4-chlorobenzoyl)-3-methylphenoxy)-2-methylpropanoate (6d1), isopropyl 2-(4-(4-chloro-2-

methylbenzoyl)-3-methylphenoxy)-2-methylpropanoate (6d2), and isopropyl 2-(4-(4-chloro-2-

methylbenzoyl)phenoxy)-2-methylpropanoate (6d3) were prepared according to General Procedure B, using isopropyl

2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate (Fenofibrate) (180 mg, 0.50 mmol) as substrate. Purification by

preparative reverse phase HPLC (45-100% MeCN in AcOH buffer, 230 nm) to give a mixture of 6d1 and 6d2 in a mole

ratio of 3.4:1.0 (43.8 mg, 23%) and 6d3 (1.7 mg, 1%) as colorless liquids (minor product, not shown in manuscript).

Or alternatively, according to General Procedure C, with the modification of heating to 60 °C, using isopropyl 2-(4-(4-

chlorobenzoyl)phenoxy)-2-methylpropanoate (Fenofibrate) (90.2 mg, 0.25 mmol) as substrate. Purification by

preparative reverse phase HPLC (50-100% MeCN in AcOH buffer, 230 nm) to give a mixture of 6d1 and 6d2 in a mole

ratio of 3.4:1.0 (43.5 mg, 46%) and 6d3 (4.8 mg, 5%) as colorless liquids (minor product, not shown in manuscript).

6d1 and 6d2: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.67 – 7.72 (m, 2.6H6h1+6h2), 7.38 – 7.44 (m, 2H6h1), 7.26 – 7.28 (m,

0.3H6h2), 7.21 – 7.24 (m, 1.6H6h1+6h2), 6.80 – 6.84 (m, 0.6H6h2), 6.75 (d, J = 2.4 Hz, 1H6h1), 6.62 (dd, J = 8.5, 2.5 Hz,

1H6h1), 5.09 (heptet, 6.3 Hz, 1H6h1), 5.07 (heptet, 6.3 Hz, 0.3H6h2) 2.35 (s, 3H6h1), 2.28 (s, 0.9H6h2), 1.65 (s, 1.8H6h2), 1.64

(s, 6H6h1), 1.22 (d, J = 6.3 Hz, 6H6h1), 1.19 (d, J = 6.3 Hz, 1.8H6h2). 13C NMR (126 MHz, CDCl3) δ (ppm) 196.5 (C6h1),

196.3 (0.3C6h2), 173.5 (C6h1), 173.1 (0.3C6h2), 160.4 (0.3C6h2) 157.8 (C6h1), 140.3 (C6h1), 139.2 (C6h1), 138.7 (0.3C6h2),

137.5 (0.3C6h2), 137.1 (C6h1), 135.8 (0.3C6h2), 132.1 (0.6C6h2), 131.5 (2C6h1), 131.4 (C6h1), 131.0 (0.3C6h2), 130.9

(0.3C6h2), 130.7 (0.3C6h2), 129.6 (0.3C6h2), 128.8 (2C6h1), 125.5 (C6h1), 121.0 (C6h1), 117.3 (0.6C6h2), 114.2 (C6h1),

79.5 (0.3C6h2), 79.3 (C6h1), 69.48 (0.3C6h2), 69.3 (C6h1), 25.5 (2C6h1), 25.5 (0.6C6h2), 21.7 (2C6h1), 21.6 (0.6C6h2), 20.8

(C6h1), 19.9 (0.3C6h2). HRMS C21H23ClO4; calcd. For (M+H+): 375.1358, found: 375.1354.

6d3: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.24 – 7.26 (m, 1H), 7.16 – 7.23 (m, 3H), 6.72 (d, J = 2.4 Hz, 1H), 6.55 (dd, J

= 8.6, 2.5 Hz, 1H), 5.08 (hept, J = 6.3 Hz, 1H), 2.47 (s, 3H), 2.32 (s, 3H), 1.62 (s, 6H), 1.20 (d, J = 6.3 Hz, 6H). 13C

NMR (126 MHz, CDCl3) δ (ppm) 198.5, 173.3, 158.5, 141.9, 139.5, 138.6, 136.3, 133.6, 131.2, 131.1, 130.8, 125.7,

121.1, 114.1, 79.3, 69.4, 25.5 (2C), 21.7, 21.7 (2C), 20.3. HRMS C22H25ClO4; calcd. For (M+H+): 389.1514, found:

389.1520.

4-amino-N-(1-(o-tolyl)-1H-pyrazol-5-yl)benzenesulfonamide (6e1) and 4-amino-N-(1-(2,6-dimethylphenyl)-1H-

pyrazol-5-yl)benzenesulfonamide (6e2) were prepared according to General Procedure B, with the modification of

heating to 100 °C, using 4-amino-N-(1-phenyl-1H-pyrazol-5-yl)benzenesulfonamide (Sulfaphenazole) (157 mg, 0.50

mmol) as substrate. Purification by preparative reverse phase HPLC (5-55% MeCN in AcOH buffer, 270 nm) to give 6e1

(32.2 mg, 20%) as a brown solid.

Or alternatively, according to General Procedure C, using 4-amino-N-(1-phenyl-1H-pyrazol-5-yl)benzenesulfonamide

(Sulfaphenazole) (78.6 mg, 0.25 mmol) as substrate. Purification by preparative reverse phase HPLC (10-55% MeCN in

AcOH buffer, 270 nm) to give 6e1 (39.0 mg, 48%) and 6e2 (12.4 mg, 14%) as brown solids.

6e1: 1H NMR (500 MHz, CD3OD) δ (ppm) 7.54 (d, J = 2.0 Hz, 1H), 7.34 – 7.41 (m, 3H), 7.31 (d, J = 7.5 Hz, 1H), 7.23

(t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.7 Hz 1H), 6.61 – 6.67 (m, 2H), 6.11 (d, J = 2.1 Hz, 1H), 1.90 (s, 3H). 13C NMR (126

MHz, CD3OD) δ (ppm) 154.5, 140.4, 138.3, 138.1, 138.0, 131.9, 130.8, 130.4 (2C), 129.4, 127.4, 126.7, 114.3 (2C),

102.4, 17.3. HRMS C16H16N4O2S; calcd. For (M+H+): 329.1067, found: 329.1065.

6e2: 1H NMR (500 MHz, CD3OD) δ (ppm) 7.55 (d, J = 1.9 Hz, 1H), 7.42 – 7.47 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.14

(d, J = 7.6 Hz, 2H), 6.61 – 6.66 (m, 2H), 6.08 (d, J = 2.1 Hz, 1H), 1.83 (s, 6H). 13C NMR (126 MHz, CD3OD) δ (ppm)

154.8, 140.8, 139.1, 138.7 (2C), 137.1, 130.8, 130.5 (2C), 129.2 (2C), 126.6, 114.2 (2C), 100.3, 17.4 (2C). HRMS

C17H18N4O2S; calcd. For (M+H+): 343.1223, found: 343.1222.

4-hydroxy-5-methyl-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one (6f) was prepared according to General Procedure

B, using 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one (Warfarin) (154 mg, 0.50 mmol) as substrate.

Purification by preparative reverse phase HPLC (20-80% MeCN in AcOH buffer, 254 nm) to give 6f (90.6 mg, 56%) as

a slightly yellow solid.

In DMSO Warfarin exists predominantly as a mixture of two diastereomers of the cyclic hemiacetal in a 2.5:1.0 ratio68.

For 6f, we observed a 3.0:1.0 ratio if isomers A (major) and B (minor).

40

1H NMR (500 MHz, DMSO-d6) δ (ppm) 7.43 (t, J = 7.5 Hz, 1.3HA+B), 7.34 (br s, 1.3HA+B), 7.08 – 7.27 (m, 9.3HA+B),

3.97 – 4.04 (m, 1.3HA+B), 2.76 (s, 4HA+B), 2.31 (dd, J = 13.7, 7.0 Hz, 1HA), 2.26 (dd, J = 13.9, 7.4 Hz, 0.33HB), 2.14 (dd,

J = 13.8, 6.2 Hz, 0.33HB), 1.85 (t, J = 12.6 Hz, 1HA), 1.65 (s, 3HA), 1.58 (s, 1HB). 13C NMR (126 MHz, CDCl3) δ (ppm)

162.1 (CB), 161.5 (CA), 160.5 (CB), 160.0 (CA), 153.6 (CB), 153.5 (CA), 144.4 (CA), 144.3 (CB), 136.6 (CB), 136.5 (CA)

131.1 (CB), 131.0 (CA) 128.2 (2CA), 127.8 (2CB), 127.5 (CB) 127.4 (CA), 127.3 (2CB) 127.0 (2CA), 125.9 (CA), 125.5

(CB), 114.7 (CB), 114.6 (CA), 114.5 (CA), 114.2 (CB), 103.3 (CA), 101.5 (CB), 100.9 (CB), 99.4 (CA), 42.5 (CA), 40.7 (CB),

35.9 (CB), 35.4 (CA), 27.3 (CA), 26.1 (CB), 23.3 (CB), 23.2 (CA). HRMS C20H18O4; calcd. For (M+H+): 323.1278, found:

323.1282.

4-amino-3-chloro-N-(2-(diethylamino)ethyl)-6-methoxy-2-methylbenzamide (6g) was prepared according to General

Procedure B, using 4-amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide hydrochloride (Metoclopramide

hydrochloride) (168 mg, 0.50 mmol) as substrate. Purification by preparative reverse phase HPLC (0-35% MeCN in

AcOH buffer, 254 nm) to give 6g (38.2 mg, 24%) as a colorless solid. 1H NMR (500 MHz, CDCl3) δ (ppm) 6.45 (br s, 1H), 6.17 (s, 1H), 4.20 (br s, 2H), 3.70 (s, 3H), 3.47 (q, J = 5.6 Hz, 2H),

2.62 (t, J = 6.0 Hz, 2H), 2.54 (q, J = 7.1 Hz, 4H), 2.30 (s, 3H), 0.99 (t, J = 7.1 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ

(ppm) 167.8, 155.4, 144.3, 135.4, 118.7, 111.9, 96.2, 55.8, 51.5, 46.6 (2C), 37.2, 17.6, 11.6 (2C). HRMS C15H24ClN3O2;

calcd. For (M+H+): 314.1630, found: 314.1634.

(R)-6-(o-tolyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (6h1) and (R)-6-(2,6-dimethylphenyl)-2,3,5,6-

tetrahydroimidazo[2,1-b]thiazole (6h2) were prepared according to General Procedure B, using (S)-6-phenyl-2,3,5,6-

tetrahydroimidazo[2,1-b]thiazole (Levamisole) (102 mg, 0.50 mmol) as substrate. Purification by preparative reverse

phase HPLC (5-45% MeCN in TFA buffer, 254 nm) to give 6h1 (35.3 mg, 32%) and 6h2 (23.3 mg, 20%) as colorless

solids.

6h1: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.33 – 7.39 (m, 1H), 7.23 – 7.27 (m, 2H), 7.15 – 7.21 (m, 1H), 5.93 (t, J = 9.0

Hz, 1H), 4.26 (t, J = 9.9 Hz, 1H), 3.78 – 3.97 (m, 3H), 3.63 – 3.74 (m, 1H), 3.47 (t, J = 8.7 Hz, 1H), 2.28 (s, 3H). 13C

NMR (126 MHz, CDCl3) δ (ppm) 177.1, 136.2, 134.6, 131.1, 128.9, 127.1, 125.4, 65.5, 54.7, 47.9, 36.0, 19.2. HRMS

C12H14N2S; calcd. For (M+H+): 219.0951, found: 219.0950.

6h2: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.13 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 7.5 Hz, 2H), 6.25 (t, J = 10.8 Hz, 1H),

4.15 (t, J = 10.5 Hz, 1H), 3.87 – 3.98 (m, 2H), 3.79 – 3.87 (m, 1H), 3.65 – 3.73 (m, 1H), 3.58 (t, J = 10.0 Hz, 1H), 2.35

(s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 176.3, 136.9 (2C), 132.3, 130.2 (2C), 129.2, 64.9, 52.7, 47.7, 35.8, 20.7

(2C). HRMS C13H16N2S; calcd. For (M+H+): 233.1107, found: 233.1108.

3-methyl-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (6i1) and 3,5-dimethyl-4-(5-(p-

tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (6i2) were prepared according to General Procedure

C, but at double scale, using 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (Celecoxib) (191

mg, 0.50 mmol) as substrate. Purification by preparative reverse phase HPLC (25-80% MeCN in AcOH buffer, 254 nm)

to give 6i1 (27.4 mg, 14%) and 6i2 (31.9 mg, 16%) as colorless solids.

6i1: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.94 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.07 – 7.14 (m,

3H), 6.73 (s, 1H), 4.78 (br s, 2H), 2.67 (s, 3H), 2.38 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 145.4, 144.1 (q, JC-F =

38.5 Hz), 142.6, 139.9, 139.4, 138.8, 129.8 (2C), 129.2, 128.9 (2C), 128.7, 125.9, 122.5, 121.2 (q, JC-F = 224.7 Hz)

106.3, 21.5, 20.5. 19F NMR (471 MHz, CDCl3) δ (ppm) -62.4 (s). HRMS C18H16F3N3O2S; calcd. For (M+H+): 396.0988,

found: 396.0992.

6i2: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.18 (d, J = 8.0 Hz, 2H), 7.10 – 7.14 (m, 4H), 6.72 (s, 1H), 4.83 (br s, 2H),

2.62 (s, 6H), 2.39 (s, 3H). 13C NMR (126 MHz, CDCl3) δ (ppm) 145.3, 144.0 (q, J = 38.5 Hz), 141.2, 140.1 (2C), 139.8,

138.5, 129.8 (2C), 128.8 (2C), 127.2 (2C), 126.0, 121.2 (q, J = 269.1 Hz), 106.2, 23.2 (2C), 21.5. 19F NMR (471 MHz,

CDCl3) δ (ppm) -62.4 (s). HRMS C19H18F3N3O2S; calcd. For (M+H+): 410.1145, found: 410.1147.

41

4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-1-(4-fluoro-2-methylphenyl)butan-1-one (6j) was prepared

according to General Procedure C, with the modification of heating to 60 °C, using 4-(4-(4-chlorophenyl)-4-

hydroxypiperidin-1-yl)-1-(4-fluorophenyl)butan-1-one (Haloperidol) (94.0 mg, 0.25 mmol) as substrate. Purification by

preparative reverse phase HPLC (5-50% MeCN in TFA buffer, 245 nm) to give 6j (43.0 mg, 44%) as a light brown solid. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.72 – 7.77 (m, 1H), 7.38 – 7.43 (m, 2H), 7.28 – 7.34 (m, 2H), 6.91 – 6.97 (m, 2H),

2.94 (t, J = 6.6 Hz, 2H), 2.83 (br s, 2H), 2.52 (s, 3H), 2.36 – 2.55 (m, 4H) , 2.09 (br s, 2H), 1.92 – 2.02 (m, 2H), 1.72 (d,

J = 13.5 Hz, 2H), 1.61 (br s, 1H). 13C NMR (126 MHz, CDCl3) δ (ppm) 202.4, 164.1 (d, JC-F = 252.7 Hz), 146.9, 142.3

(d, JC-F = 8.6 Hz), 134.2, 133.0, 131.4 (d, JC-F = 9.3 Hz), 128.6 (2C), 126.2 (2C), 118.9 (d, JC-F = 21.1 Hz), 112.6 (d, JC-F

= 21.3 Hz), 71.2, 57.9, 49.5 (2C), 39.2, 38.4 (br s, 2C), 21.9, 21.8. 19F NMR (471 MHz, CDCl3) δ (ppm) -108.4 (s).

HRMS C22H25ClFNO2; calcd. For (M+H+): 390.1631, found: 390.1634.

(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-5-methyl-1,3-dioxoisoindolin-4-yl)acetamide

(6k) was prepared according to General Procedure C, using (S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-

(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide (Apremilast) (115 mg, 0.25 mmol) as substrate. Purification

by preparative reverse phase HPLC (15-55% MeCN in TFA buffer, 230 nm) to give 6k (27.2 mg, 23%) as a colorless

liquid. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.22 (br s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.05 – 7.09 (m,

2H), 6.8 – 6.85 (m, 1H), 5.84 (dd, J = 10.2, 4.5 Hz, 1H), 4.51 (dd, J = 14.3, 10.4 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.84

(s, 3H), 3.73 (dd, J = 14.4, 4.5 Hz, 1H), 2.83 (s, 3H), 2.33 (s, 3H), 2.26 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H). 13C NMR (126

MHz, CDCl3) δ (ppm) 169.1, 168.3, 167.5, 149.8, 148.7, 142.8, 137.4, 134.4, 129.5, 129.4, 122.8, 121.1, 120.4, 112.5,

111.5, 64.6, 56.1, 54.8, 48.7, 41.7, 23.9, 19.7, 14.8. HRMS C23H26N2O7S; calcd. For (M+H+): 475.1534, found:

475.1535.

8-fluoro-9-methyl-5-(4-((methylamino)methyl)phenyl)-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-1-one (6l) was

prepared according to General Procedure C, with the modification of heating to 60 °C, using 8-fluoro-5-(4-

((methylamino)methyl)phenyl)-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-1-one (Rucaparib) (81 mg, 0.25 mmol) as

substrate. Purification by preparative reverse phase HPLC (15-60% MeCN in NH3 buffer, 280 nm) to give 61 (32.8 mg,

39%) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 11.48 (s, 1H), 8.21 (t, J = 6.6 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1

Hz, 2H), 7.24 (d, JH-F = 10.1 Hz, 1H), 3.69 (s, 2H), 3.31 (br s, 3H), 2.83 – 3.08 (m, 2H), 2.43 (d, JH-F = 2.8 Hz, 3H), 2.29

(s, 3H). 13C NMR (126 MHz, DMSO-d6) δ (ppm) 168.8 (d, JC-F = 3.1 Hz), 157.8 (d, JC-F = 234 Hz), 140.2, 135.4 (d, JC-F

= 3.4 Hz), 134.3 (d, JC-F = 13.5 Hz), 130.0, 128.3 (2C), 127.6 (2C), 124.9 (d, JC-F = 5.0 Hz), 122.8, 118.9 (d, JC-F = 19.2

Hz), 111.0, 99.4 (d, JC-F = 28.4 Hz), 54.7, 42.0, 35.6, 29.7, 13.0 (d, JC-F = 6.6 Hz). 19F NMR (471 MHz, DMSO-d6) δ

(ppm) -122.1 (s). HRMS C20H20FN3O; calcd. For (M+H+): 338.1663, found: 338.1677.

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (6m1), N-(2,4-di-tert-

butyl-5-hydroxyphenyl)-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (6m2), and N-(2,4-di-tert-butyl-5-

hydroxyphenyl)-2,5-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (6m3) were prepared according to General

Procedure C, but at double scale, using N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-

carboxamide (Ivacaftor) (196 mg, 0.50 mmol) as substrate. Purification by preparative reverse phase HPLC (40-100%

42

MeCN in AcOH buffer, 254 nm) to give 6m1 (24.6 mg, 12%), 6m2 (17.7 mg, 9%), and 6m3 (15.3 mg, 7%) as slightly

yellow solids. The compounds were obtained with approximately 90% purity.

6m1: 1H NMR (500 MHz, DMSO-d6) δ (ppm) 12.36 (br s, 1H), 12.22 (s, 1H), 9.11 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H),

7.76 (t, J = 7.7 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.15 (s, 1H), 7.01 (s, 1H), 2.88 (s, 3H), 1.36 (s,

9H), 1.35 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ (ppm) 176.8, 164.4, 156.8, 153.2, 138.0, 134.0, 132.8, 132.7,

131.3, 125.6, 124.8, 124.6, 123.6, 118.1, 116.5, 110.1, 34.3, 34.0, 30.6 (3C), 29.4 (3C), 21.9. HRMS C25H30N2O3; calcd.

For (M+H+): 407.2329, found: 407.2327.

6m2: 1H NMR (500 MHz, DMSO-d6) δ (ppm) 12.62 (d, J = 6.4 Hz, 1H), 11.90 (s, 1H), 9.16 (s, 1H), 8.75 (d, J = 6.6 Hz,

1H), 7.61 (t, J = 7.7 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.16 (s, 1H), 7.09 (s, 1H), 2.89 (s, 3H),

1.37 (s, 9H), 1.36 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ (ppm) 179.3, 163.0, 153.3, 143.2, 140.8, 140.2, 133.7,

132.3, 132.0, 131.4, 127.7, 124.5, 123.7, 117.2, 115.9, 111.9, 34.3, 33.9, 30.5 (3C), 29.4 (3C), 23.7. HRMS C25H30N2O3;

calcd. For (M+H+): 407.2329, found: 407.2333.

6m3: 1H NMR (500 MHz, DMSO-d6) δ (ppm) 12.10 (s, 1H), 12.04 (s, 1H), 9.10 (s, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.47

(d, J = 8.2 Hz, 1H), 7.12 – 7.18 (m, 2H), 7.05 (s, 1H), 2.84 (s, 3H), 2.80 (s, 3H), 1.36 (s, 9H), 1.35 (s, 9H). 13C NMR

(126 MHz, DMSO-d6) δ (ppm) 179.5, 164.5, 155.2, 153.2, 139.8, 139.6, 134.1, 132.6, 131.8, 131.2, 127.2, 123.6, 123.2,

116.3, 116.2, 111.4, 34.3, 34.0, 30.6 (3C), 29.4 (3C), 23.5, 21.3. HRMS C26H32N2O3; calcd. For (M+H+): 421.2486,

found: 421.2490.

4-(4-chlorobenzyl)-8-methyl-2-(1-methylazepan-4-yl)phthalazin-1(2H)-one (6n) was prepared according to General

Procedure C, with the modification of heating to 80 °C, using 4-(4-chlorobenzyl)-2-(1-methylazepan-4-yl)phthalazin-

1(2H)-one (95.5 mg, 0.25 mmol) as substrate. Purification by preparative reverse phase HPLC (40-100% MeCN in NH3

buffer, 290 nm) to give 6n (24.8 mg, 25%) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.49 – 7.57 (m, 2H), 7.44 (d, J = 6.9 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.18 (d, J =

8.4 Hz, 2H), 5.27 – 5.36 (m, 1H), 4.22 (s, 2H), 2.93 (s, 3H), 2.78 – 2.87 (m, 1H), 2.72 (br s, 2H), 2.58 – 2.66 (m, 1H),

2.43 (s, 3H), 2.17 – 2.27 (m, 1H), 2.00 – 2.14 (m, 3H), 1.90 – 2.00 (m, 1H), 1.72 – 1.83 (m, 1H). 13C NMR (126 MHz,

CDCl3) δ (ppm) 159.5, 144.5, 142.1, 136.7, 134.3, 132.5, 132.4, 130.1 (3C), 128.9 (2C), 126.3, 122.8, 58.8, 55.6, 54.4,

46.8, 38.8, 32.9, 32.3, 24.4, 23.6. HRMS C23H26ClN3O; calcd. For (M+H+): 396.1837, found: 396.1843.

methyl ((5S,10S,11S,14S)-11-benzyl-5-(tert-butyl)-8-(3,5-dimethyl-4-(pyridin-2-yl)benzyl)-10-hydroxy-15,15-

dimethyl-3,6,13-trioxo-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate (6o) was prepared according to General

Procedure C, but at reduced scale, using methyl ((5S,10S,11S,14S)-11-benzyl-5-(tert-butyl)-10-hydroxy-15,15-dimethyl-

3,6,13-trioxo-8-(4-(pyridin-2-yl)benzyl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate (Atazanavir) (141 mg, 0.20

mmol) as substrate. Purification by preparative reverse phase HPLC (25-75% MeCN in AcOH buffer, 230 nm) to give 6o

(80.2 mg, 55%) as a light brown solid. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.10 (s, 1H), 8.72 (d, J = 4.5 Hz, 1H), 8.01 (br s, 1H), 7.56 (d, J = 9.0 Hz, 1H),

7.48 (br s, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.17 – 7.21 (m, 4H), 7.10 – 7.17 (m, 1H), 7.08 (s, 2H), 7.03 (d, J = 9.3 Hz, 1H),

6.88 (d, J = 9.4 Hz, 1H), 5.01 (br s, 1H), 3.97 – 4.08 (m, 1H), 3.83 – 3.95 (m, 3H), 3.68 (d, J = 9.4 Hz, 1H), 3.60 (d, J =

8.1 Hz, 1H), 3.53 (s, 6H) 2.68 – 2.85 (m, 3H), 2.59 – 2.66 (m, 1H), 1.95 (s, 6H), 0.78 (s, 9H), 0.66 (s, 9H). 13C NMR

(126 MHz, DMSO-d6) δ (ppm) 170.2, 170.0, 158.0 (br s), 156.5 (2C), 148.5 (br s), 139.0, 138.1 (br s, 2C), 137.3, 134.8

(2C), 129.0 (2C), 128.0 (2C), 127.5 (2C), 125.8, 125.0 (br s), 122.5 (br s), 68.1, 63.0, 61.2, 60.8, 60.7, 51.7, 51.4, 51.4,

37.7, 33.7, 33.4, 26.6 (3C), 26.2 (3C), 19.9 (2C). HRMS C40H56N6O7; calcd. For (M+H+): 733.4283, found: 733.4292.

43

XI. NMR spectra and HPLC chromatograms

Cp*Co(CO)I2

44

Cp*Co(PhH)(PF6)2 (4a)

45

46

2-(o-tolyl)pyridine (3a1) and 2-(2,6-dimethylphenyl)pyridine (3a2) (1.0:2.0 ratio)

2-(o-tolyl)pyridine (3a1)

47

2-(2,6-dimethylphenyl)pyridine (3a2)

48

2-(2-ethyl-6-methylphenyl)pyridine (3a3)

49

1-(o-tolyl)-1H-pyrazole (3b1) and 1-(2,6-dimethylphenyl)-1H-pyrazole (3b2) (1.0:1.6 ratio)

50

1-(o-tolyl)-1H-pyrazole (3b1)

51

1-(2,6-dimethylphenyl)-1H-pyrazole (3b2)

52

2-phenylthiazole (1c) and 2-(o-tolyl)thiazole (3c1) and 2-(2,6-dimethylphenyl)thiazole (3c2) (1.3:1.0:1.4 ratio)

2-(o-tolyl)thiazole (3c1)

53

2-(2,6-dimethylphenyl)thiazole (3c2)

54

3-chloro-6-phenylpyridazine (1d) and 3-chloro-6-(o-tolyl)pyridazine (3d1) and 3-chloro-6-(2,6-

dimethylphenyl)pyridazine (3d2) (2.1:5.6:1.0 ratio)

55

3-chloro-6-(o-tolyl)pyridazine (3d1)

56

3-chloro-6-(2,6-dimethylphenyl)pyridazine (3d2)

57

2-phenyl-4,5-dihydrooxazole (1e) and 2-(2,6-dimethylphenyl)-4,5-dihydrooxazole (3e2) (1.8:1.0 ratio)

2-(o-tolyl)-4,5-dihydrooxazole (3e1)

58

2-(2,6-dimethylphenyl)-4,5-dihydrooxazole (3e2)

59

N,2-dimethylbenzamide (3f1) and N,2,6-trimethylbenzamide (3f2) (6.0:1.0 ratio)

60

N,2-dimethylbenzamide (3f1)

61

N,2,6-trimethylbenzamide (3f2)

62

N-(tert-butyl)-2-methylbenzamide (3g1) and N-(tert-butyl)-2,6-dimethylbenzamide (3g2) (3.4:1.0 ratio)

N-(tert-butyl)-2-methylbenzamide (3g1)

63

N-(tert-butyl)-2,6-dimethylbenzamide (3g2)

64

3,4-dihydroisoquinolin-1(2H)-one (1h) and 8-methyl-3,4-dihydroisoquinolin-1(2H)-one (3h) (1.0:3.1 ratio)

65

8-methyl-3,4-dihydroisoquinolin-1(2H)-one (3h)

66

2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (1i) and 9-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (3i)

(1.0:1.7 ratio)

9-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (3i)

67

N,3-dimethylthiophene-2-carboxamide (3j1) and N,3,5-trimethylthiophene-2-carboxamide (3j2) (11.0:1.0 ratio)

68

N,3-dimethylthiophene-2-carboxamide (3j1)

69

N,3,5-trimethylthiophene-2-carboxamide (3j2)

70

3-methylbenzamide (1k) and 2,5-dimethylbenzamide (3k) (1.0:2.7 ratio)

2,5-dimethylbenzamide (3k)

71

2-(2-hydroxyethoxy)benzamide (1l) and 2-(2-hydroxyethoxy)-6-methylbenzamide (3l) (1.0:2.7 ratio)

72

2-(2-hydroxyethoxy)-6-methylbenzamide (3l)

73

2-chloro-6-methoxyisonicotinamide (1m) and 6-chloro-2-methoxy-3-methylisonicotinamide (3m) (1.3:1.0 ratio)

6-chloro-2-methoxy-3-methylisonicotinamide (3m)

74

N,N-dimethylbenzamide (1n) and N,N,2-trimethylbenzamide (3n) (1.0:7.5 ratio)

75

N,N,2-trimethylbenzamide (3n)

76

(4-bromophenyl)(pyrrolidin-1-yl)methanone (1o) and (4-bromo-2-methylphenyl)(pyrrolidin-1-yl)methanone (3o)

(1.0:1.0 ratio)

(4-bromo-2-methylphenyl)(pyrrolidin-1-yl)methanone (3o)

77

N-(o-tolyl)acetamide (3p)

78

1-(4-(dimethylamino)phenyl)ethan-1-one (1q) and 1-(4-(dimethylamino)-2-methylphenyl)ethan-1-one (3q1) and 1-

(4-(dimethylamino)-2,6-dimethylphenyl)ethan-1-one (3q2) (1.0:4.2:3.1 ratio)

79

1-(4-(dimethylamino)-2-methylphenyl)ethan-1-one (3q1)

80

1-(4-(dimethylamino)-2,6-dimethylphenyl)ethan-1-one (3q2)

81

5-methyl-2-phenyl-4H-chromen-4-one (3r)

82

4-(dimethylamino)-2-methoxy-6-methylbenzaldehyde (3s)

83

6-methoxy-8-methylquinoline (3t)

84

4-chloro-8-methylnaphthalen-1-ol (3u)

85

naphthalen-1-amine (1v) and 8-methylnaphthalen-1-amine (3v) (1.0:1.0 ratio)

8-methylnaphthalen-1-amine (3v)

86

8-methylquinoline (1w) and 8-ethylquinoline (3w) (1.0:1.1)

87

8-ethylquinoline (3w)

88

N-(3-methyl-4-(pyridin-2-yl)phenyl)acetamide (3x1) and N-(3,5-dimethyl-4-(pyridin-2-yl)phenyl)acetamide (3x2)

(1.0:0.95 ratio)

N-(3-methyl-4-(pyridin-2-yl)phenyl)acetamide (3x1)

89

N-(3,5-dimethyl-4-(pyridin-2-yl)phenyl)acetamide (3x2)

90

3-acetylbenzamide (1y) and 5-acetyl-2-methylbenzamide (3y)

(0.1:1.0 ratio)

91

5-acetyl-2-methylbenzamide (3y)

92

N-phenylbenzamide (1z) and 2-methyl-N-phenylbenzamide (3z1) and 2,6-dimethyl-N-phenylbenzamide (3z2)

(2.0:2.6:1.0 ratio)

2-methyl-N-phenylbenzamide (3z1)

93

2,6-dimethyl-N-phenylbenzamide (3z2)

94

95

7-chloro-1-methyl-5-(o-tolyl)-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (6a1)

96

7-chloro-5-(2,6-dimethylphenyl)-1-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (6a2)

97

(4aR,4a1R,5aS,8aR,8a1S,15aS)-12-methyl-2,4a,4a1,5,5a,7,8,8a1,15,15a-decahydro-14H-4,6-methanoindolo[3,2,1-

ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one (6b)

98

(2aR,4S,4aS,6R,9S,11S,12S,12bS)-12-(benzoyloxy)-4,11-dihydroxy-9-(((2R,3S)-2-hydroxy-3-(2-methylbenzamido)-

3-phenylpropanoyl)oxy)-4a,8,13,13-tetramethyl-5-oxo-3,4,4a,5,6,9,10,11,12,12a-decahydro-1H-7,11-

methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b(2aH)-diyl diacetate (6c)

99

isopropyl 2-(4-(4-chlorobenzoyl)-3-methylphenoxy)-2-methylpropanoate (6d1) and isopropyl 2-(4-(4-chloro-2-

methylbenzoyl)-3-methylphenoxy)-2-methylpropanoate (6d2)

100

isopropyl 2-(4-(4-chloro-2-methylbenzoyl)phenoxy)-2-methylpropanoate (6d3)

101

4-amino-N-(1-(o-tolyl)-1H-pyrazol-5-yl)benzenesulfonamide (6e1)

102

4-amino-N-(1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl)benzenesulfonamide (6e2)

103

4-hydroxy-5-methyl-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one (6f)

104

4-amino-3-chloro-N-(2-(diethylamino)ethyl)-6-methoxy-2-methylbenzamide (6g)

105

(R)-6-(o-tolyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (6h1)

106

(R)-6-(2,6-dimethylphenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (6h2)

107

3-methyl-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (6i1)

108

3,5-dimethyl-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (6i2)

109

110

4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-1-(4-fluoro-2-methylphenyl)butan-1-one (6j)

111

(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-5-methyl-1,3-dioxoisoindolin-4-yl)acetamide (6k)

112

8-fluoro-9-methyl-5-(4-((methylamino)methyl)phenyl)-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-1-one (6l)

113

114

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (6m1)

115

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (6m2)

116

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-2,5-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (6m3)

117

4-(4-chlorobenzyl)-8-methyl-2-(1-methylazepan-4-yl)phthalazin-1(2H)-one (6n)

118

methyl ((5S,10S,11S,14S)-11-benzyl-5-(tert-butyl)-8-(3,5-dimethyl-4-(pyridin-2-yl)benzyl)-10-hydroxy-15,15-

dimethyl-3,6,13-trioxo-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate (6o)

119

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